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The keto‐switched photocatalysis of covalent organic frameworks (COFs) for efficient H2 evolution was reported for the first time by engineering, at a molecular level, the local structure and component of the skeletal building blocks. A series of imine‐linked BT‐COFs were synthesized by the Schiff‐base reaction of 1, 3, 5‐benzenetrialdehyde with diamines to demonstrate the structural reconstruction of enol to keto configurations by alkaline catalysis. The keto groups of the skeletal building blocks served as active injectors, where hot π‐electrons were provided to Pt nanoparticles (NPs) across a polyvinylpyrrolidone (PVP) insulting layer. The characterization results, together with density functional theory calculations, indicated clearly that the formation of keto‐injectors not only made the conduction band level more negative, but also led to an inhomogeneous charge distribution in the donor‐acceptor molecular building blocks to form a strong intramolecular built‐in electric field. As a result, visible‐light photocatalysis of TP‐COFs‐1 with one keto group in the skeletal building blocks was successfully enabled and achieved an impressive H2 evolution rate as high as 0.96 mmol g−1 h−1. Also, the photocatalytic H2 evolution rates of the reconstructed BT‐COFs‐2 and ‐3 with two and three keto‐injectors were significantly enhanced by alkaline post‐treatment. [ABSTRACT FROM AUTHOR]

The keto‐switched photocatalysis of covalent organic frameworks (COFs) for efficient H2 evolution was reported for the first time by engineering, at a molecular level, the local structure and component of the skeletal building blocks. A series of imine‐linked BT‐COFs were synthesized by the Schiff‐base reaction of 1, 3, 5‐benzenetrialdehyde with diamines to demonstrate the structural reconstruction of enol to keto configurations by alkaline catalysis. The keto groups of the skeletal building blocks served as active injectors, where hot π‐electrons were provided to Pt nanoparticles (NPs) across a polyvinylpyrrolidone (PVP) insulting layer. The characterization results, together with density functional theory calculations, indicated clearly that the formation of keto‐injectors not only made the conduction band level more negative, but also led to an inhomogeneous charge distribution in the donor‐acceptor molecular building blocks to form a strong intramolecular built‐in electric field. As a result, visible‐light photocatalysis of TP‐COFs‐1 with one keto group in the skeletal building blocks was successfully enabled and achieved an impressive H2 evolution rate as high as 0.96 mmol g−1 h−1. Also, the photocatalytic H2 evolution rates of the reconstructed BT‐COFs‐2 and ‐3 with two and three keto‐injectors were significantly enhanced by alkaline post‐treatment. [ABSTRACT FROM AUTHOR]

Fracture reorientation can be used to increase well production in an anisotropic reservoir. The principal focus of this work is on the transient pressure analysis for a hydraulic reorientation fracture in a rectangular anisotropic reservoir. By employing the nodal analysis technique, a set of diffusivity equations are developed to describe the flow in a hydraulic reorientation fracture. Then, a semi-analytical solution is obtained by coupling the point source solution and the discrete fracture solution. The validation of this work is demonstrated by comparing the previous study and the numerical simulation for a reorientation fracture. Five typical flow regimes can be observed on this model's transient response. Flux along the reorientation fracture is also generated to analyze the flux distribution at different time. Furthermore, type curves are obtained to investigate the effect of the key parameters on the transient flow behavior, including principal fracture angle, reoriented fracture angle, permeability anisotropy, fracture conductivity and fracture length ratio. For a rectangular anisotropic reservoir, the influence of principal fracture angle, permeability anisotropy and fracture conductivity on the type curves is concentrated in the early-time and middle-time periods, and reoriented fracture angle and fracture length ratio mainly affect the formation linear flow regime. • a new semi-analytical solution of a reorientation fracture with finite conductivity in an anisotropic reservoir. • Reoriented fracture mainly affect the formation linear flow regime. • Fracture length ratio should be as small as possible for high well productivity. • The principal fracture and reoriented fracture angle should be perpendicular to the maximum permeability direction. [ABSTRACT FROM AUTHOR]

• The OVA sensitized AR mouse model and EOL-1 cells model are established. • The level of miR-223-3p is up-regulated in AR patients and AR mice. • MiR-223-3p affects AR inflammatory response by promoting eosinophil degranulation. • FBXW7 is a target gene of miR-223-3p, and its expression is low in AR group. • MiR-223-3p affects eosinophil degranulation and AR inflammation by targeting FBXW7. MiR-223-3p is a multifunctional microRNA regulated by multiple transcription factors and plays a critical role in inflammation. This paper was designed to investigate the regulatory role and mechanism of miR-223-3p in eosinophils degranulation and allergic rhinitis (AR) inflammation. OVA sensitized AR mouse model and EOL-1 cells model were established. RT-qPCR and FISH were performed to detect the miR-223-3p expression. ELISA and WB were utilized to evaluate mRNA and protein expression. HE staining and transmission electron microscopy were applied to observe the morphological changes in nasal mucosa. Flow cytometry and immunofluorescence staining were performed to measure the proportion of eosinophils and eosinophilic major basic protein expression. The targeting relationship between miR-223-3p and FBXW7 was verified by bioinformatic analysis and dual-luciferase reporter gene assay. The expression of FBXW7 was detected by immunohistochemistry. The level of miR-223-3p in nasal mucosa was significantly up-regulated in AR group. The expression of miR-223-3p, ECP, MBP, and EPO were increased in EOL-1 cells, further increasing the miR-223-3p level could promote the ECP and EPO mRNA expression. Upregulation of miR-223-3p increased eosinophils granule protein expression, aggravated mucosal destruction and enhanced AR inflammation. Luciferase assay verified miR-223-3p directly target the 3ʹ-UTR of FBXW7. In vitro, overexpression of FBXW7 could reverse the increase in MBP expression caused by the up-regulation of miR-223-3p. In vivo, knockdown of FBXW7 could reverse the down-regulation in granule protein level caused by the down-regulation of miR-223-3p, thereby aggravating AR inflammation. Collected evidence elucidated that miR-223-3p could regulate the eosinophil degranulation and enhances the inflammation in AR by targeting FBXW7. The miR-223-3p/FBXW7 axis may provide a novel approach for AR treatment. [ABSTRACT FROM AUTHOR]

This paper examines linear algebraic solvers for a given general purpose compositional simulator. In particular, the decoupling stage of the constraint pressure residual (CPR) preconditioner for linear systems arising from the fully implicit scheme is evaluated. An asymptotic analysis of the convergence behavior is given when Δ t approaches zero. Based on this analysis, we propose an analytical decoupling technique, from which the pressure equation is directly related to an elliptic equation and can be solved efficiently. We show that this method ensures good convergence behavior of the algebraic solvers in a two-stage CPR-type preconditioner. We also propose a semi-analytical decoupling strategy that combines the analytical method and alternate block factorization method. Numerical experiments demonstrate the superior performance of the analytical and semi-analytical decoupling methods compared to existing methods. [ABSTRACT FROM AUTHOR]

Numerical simulation based on fine-scale reservoir models helps petroleum engineers in understanding fluid flow in porous media and achieving higher recovery ratio. Fine-scale models give rise to large-scale linear systems, and thus require effective solvers for solving these linear systems to finish simulation in reasonable turn-around time. In this paper, we study convergence, robustness, and efficiency of a class of multi-stage preconditioners accelerated by Krylov subspace methods for solving Jacobian systems from a fully implicit discretization. We compare components of these preconditioners, including decoupling and sub-problem solvers, for fine-scale reservoir simulation. Several benchmark and real-world problems, including a ten-million-cell reservoir problem, were simulated on a desktop computer. Numerical tests show that the combination of the alternating block factorization method and multi-stage subspace correction preconditioner gives a robust and memory-efficient solver for fine-scale reservoir simulation. [ABSTRACT FROM AUTHOR]

Oncrasins are a class of RNA polymerase II inhibitors. Oncrasin-72 is an indole-3 carbinol analog that has shown to inhibit growth and induce the cell death of various human cancer cell lines. Oncrasin-266, a prodrug of oncrasin-72, has been shown to have improved pharmacokinetic properties and safety than Oncrasin-72. With respect to the potential therapeutic advantages of this class of compounds, there is a need for further preclinical assessment for future clinical trials. The development of and validation of an analytical method is essential for the quantification of oncrasins in biological fluids for pharmacokinetic studies. This study focuses on the HPLC–MS/MS method development and validation of oncrasin-266, oncrasin-72 and its aldehyde metabolite in rat plasma. Blank rat plasma, coupled with 1-(3-chlorobenzyl)-1H-indole, as internal standard, was used for generating standard curves ranging from 1 to 250 ng/mL for oncrasin-266 and oncrasin-72; and 0.5–125 ng/mL for the aldehyde metabolite. The chromatographic separation was achieved by a Zorbax 300SB-C 18 HPLC column at 50°C with a flow rate of 1.1 mL/min under gradient elution. Mass detection was performed under positive ionization electrospray. Intra- and inter-day accuracy and precision of the assay were less than 10%. We report a simple, specific and reproducible HPLC–MS/MS method for the quantification of oncrasins in rat plasma. This study was successfully used for the quantification of oncrasins in rat plasma for pharmacokinetic studies in three dose groups of 10, 25, and 50 mg/kg via intravenous administration. [ABSTRACT FROM AUTHOR]

Through synthetic lethality screening of isogenic cell lines with and without the oncogenic KRAS gene and through lead compound optimization, we recently developed a novel anticancer agent designated NSC-743380 (oncrasin-72) that has promising in vitro and in vivo anticancer activity in a subset of cancer cell lines, including KRAS -mutant cancer cells. However, NSC-743380 tends to form dimers, which dramatically reduces its anticancer activity. To improve the physicochemical properties of NSC-743380, we synthesized a prodrug of NSC-743380, designated oncrasin-266, by modifying NSC-743380 with cyclohexylacetic acid and evaluated its in vitro and in vivo properties. Oncrasin-266 spontaneously hydrolyzed in phosphate-buffered saline in a time-dependent manner and was more stable than NSC-743380 in powder or stock solutions. In vivo administration of oncrasin-266 in mice led to the release of NSC-743380 which improved the pharmacokinetics of NSC-743380. Tissue distribution analysis revealed that oncrasin-266 was deposited in liver, whereas released NSC-743380 was detected in liver, lung, kidney, and subcutaneous tumor. Oncrasin-266 was better tolerated in mice at a higher dose level treatment (150–300 mg/kg, ip) than the parent agent was, suggesting that the prodrug reduced the acute toxicity of the parent agent. Our results demonstrated that the prodrug strategy could improve the stability, pharmacokinetic properties, and safety of NSC-743380. [ABSTRACT FROM AUTHOR]

Based on the surface 2 m monthly minimum temperature from the National Centers for Environmental Prediction/National Center for Atmospheric Research reanalysis dataset, the spatial and temporal characteristics of winter minimum temperature during 1961-2010 have been analyzed in China. Results showed that the minimum temperature in China has a significant increasing rate of 0.25° per decade calculated by the Mann-Kendall statistical test, which is consistent with the global warming trend. Empirical orthogonal function (EOF) analysis reveals that there are three main patterns that can explain more than 57.6% of the total variance of the winter minimum temperature. The EOF1, EOF2, and EOF3 account for 34.8%, 13.5%, and 13.5% of the total inter-annual variance, respectively. The EOF1, EOF2, and EOF3 patterns are synchronous in northern China, central China, and on the Tibetan Plateau. There exist a decrease trend in the corresponding time coefficients of EOF1 and EOF2 and an increase trend in that of EOF3 since the 1960s. Both the corresponding time coefficients of EOF1 and EOF2 have significant positive correlations with the 500 hPa geopotential heights of the Arctic region and negative correlations in the regions lower than 40°N, while a significant positive correlation is found between the corresponding time coefficients of EOF3 and 500 hPa geopotential heights in the low latitudes. This suggests that rapid warming occurs in northern China and on the Tibetan Plateau, while the weakest trend locates in southeast China. Thus, warming in winter is more pronounced at higher altitudes and latitudes. These patterns are tightly connected with the atmospheric circulation. [ABSTRACT FROM AUTHOR]

Abstract: Recombinant adenoviral vectors (adenovectors) have been subject to various genetic modifications to improve their transduction efficiency and targeting capacity. Production and purification of adenovectors with modified capsid proteins can be problematic using conventional two-cycle CsCl gradient ultracentrifugation. We have developed a new method for purifying recombinant adenovectors in two steps: iodixanol discontinuous density gradient ultracentrifugation and size exclusion column chromatography. The purity and infectious activity of adenovectors isolated by the two methods were comparable. The new method yielded three to four times more adenovectors with arginine–glycine–aspartic acid (RGD)-modified fiber proteins than did the conventional CsCl method. For other fiber-modified and wild-type adenovectors, the yields of the two methods were comparable. Thus, the iodixanol-based method can be used not only to improve the production of RGD-modified adenovectors but also to purify adenovectors with or without fiber modifications. Moreover, the whole procedure can be completed in 3h. Therefore, this method is rapid and efficient for production of recombination adenovectors, especially those with RGD-modified fibers. [Copyright &y& Elsevier]

The eco-system in the Qinghai-Tibet Plateau (QTP) is extremely fragile, and highly vulnerable to climate change. Knowledge of the changes in the ecological conditions is vital to mitigate the impact of climate change. In this study, we investigated the trend of ecological conditions of the QTP using the remotely sensed ecological index (RSEI), which is the first PCA (principal component analysis) axis of the four indexes derived from the MODIS (Moderate resolution Imaging Spectroradiometer) images captured in the growing season of 2000–2020. The four indexes, i.e., NDVI (normalized difference vegetation index), heat (land surface temperature, LST), wetness (tasseled cap wetness index, WET) and dryness (normalized difference impervious surface index, NDBSI), were calculated on the Google Earth Engine platform. Using land use cover change (LUCC) data, long-term meteorological records and the supplementary annual livestock production, we explored the drivers of spatiotemporal changes in the RSEI. The results show the following points: (1) the ecological conditions of the QTP have remarkable spatiotemporal variations. There were two ecological degradation periods, one of them occurred in the central region during 2005–2010, mainly attributed to the rising temperatures and decreasing precipitation. The other occurred during 2015–2020, driven primarily by overgrazing in the southwest. From 2000 to 2005, it was a period of rapid ecological restoration in the ecologically fragile northeast region. (2) The contribution rate of pc1 was stable at 60%, while the contribution rate of pc2 remained below 40%, indicating that pc1 demonstrated most of the characteristics of the four indexes. The correlation coefficients between NDVI and WET with pc1 are both positive, while LST and NDBSI have negative correlation coefficients, i.e., negative effects. This is consistent with the actual situation. (3) Overgrazing caused grass degradation in the southwest area of the QTP, which might be the main reason for the poor ecological conditions (i.e., low RSEI value) during 2015–2020. (4) Temperature and precipitation showed an increasing trend during the study period. A warmer and wetter climate is expected to have profound impacts on the ecosystems in QTP and practices should be concentrated on identifying climate-sensitive ecosystem components and designating adaptative options. [ABSTRACT FROM AUTHOR]

Nasopharyngeal carcinoma (NPC) is a tumor that occurs in the nasopharynx. Although advances in detection and treatment have improved the prognosis of NPC the treatment of advanced NPC remains challenging. Here, we explored the effect of microRNA (miR)-122-5p on erastin-induced ferroptosis in NPC cells and the role of ferroptosis in the development of NPC. The effect of miR-122-5p silencing and overexpression and the effect of citrate synthase on erastin-induced lipid peroxidation in NPC cells was analyzed by measuring the amounts of malondialdehyde, Fe2+, glutathione, and reactive oxygen species and the morphological alterations of mitochondria. The malignant biological behavior of NPC cells was examined by cell counting kit-8, EDU, colony formation, Transwell, and wound healing assays. The effects of miR-122-5p on cell proliferation and migration associated with ferroptosis were examined in vivo in a mouse model of NPC generated by subcutaneous injection of NPC cells. We found that erastin induced ferroptosis in NPC cells. miR-122-5p overexpression inhibited CS, thereby promoting erastin-induced ferroptosis in NPC cells and decreasing NPC cell proliferation, migration, and invasion. [ABSTRACT FROM AUTHOR]

• A murine model of allergic rhinitis inducing by ovalbumin is constructed. • Administer lentiviral shRNA targeting CCR3 gene into the CCR3shRNA treated group. • The bone marrow, peripheral blood, nasal mucosa of mice are collected and assessed. • Explore the effect of CCR3-silencing on function of mast cells in AR mice in vivo. • CCR3shRNA downgrade the CCR3 gene in bone marrow, peripheral blood and nasal mucosa. • Inhibition of CCR3 gene expression can alleviate the inflammation of allergic rhinitis. The CC chemokine receptor 3 (CCR3) expressed by eosinophils, mast cells and Th2 cells is closely related to allergic diseases. The objective of this study was to explore whether silencing of CCR3 with short hairpin RNAs (shRNAs) delivered by a lentiviral vector could impact the function of mast cells in a murine model of allergic rhinitis (AR) in vivo. The murine model of allergic rhinitis (AR) inducing by ovalbumin (OVA) was constructed, and the BALB/c mice were divided into normal control group, AR group, controlshRNA treated group and lentiviral CCR3-shRNA treated group. The recombinant lentivirus vectors which express a short hairpin RNA (shRNA) targeting the CCR3 were dropped into the nasal cavity of OVA-sensitized mice before the challenges. Real-time fluorescence quantitative PCR and western blotting were performed to observe inhibitory effect of CCR3 gene. Nasal symptoms of mice and OVA-specific IgE in each group were assessed. Concentrations of histamine, tryptase and Prostaglandin D2 (PGD2) in bone marrow, peripheral blood and nasal mucosa were analyzed. Furthermore, histological analysis and electron microscopy analysis were applied to detect the histology changes of nasal mucosa and the infiltration of mast cells in nasal mucosa. The results showed that administration of CCR3shRNA could effectively inhibit the expression of the CCR3 gene in bone marrow, peripheral blood and nasal mucosa, which reduced the nasal symptoms, the level of OVA-specific IgE, the inflammatory cells and mast cells infiltration into nasal cavity, and relieved the histopathological changes of nasal mucosa. In addition, intervention of CCR3shRNA could reduce the levels of the histamine, tryptase and PGD2 in bone marrow, peripheral blood and nasal mucosa. These results suggest that inhibition of CCR3 gene expression by shRNAs lentiviral vectors can effectively attenuate migration, infiltration and degranulation of mast cells in local tissues and alleviate the inflammation of allergic rhinitis mice. [ABSTRACT FROM AUTHOR]

A fractured horizontal well is an effective technology to obtain hydrocarbons from tight reservoirs. In this study, a new semi-analytical model for a horizontal well intercepted by multiple finite-conductivity reorientation fractures was developed in an anisotropic rectangular tight reservoir. Firstly, to establish the flow equation of the reorientation fracture, all reorientation fractures were discretized by combining the nodal analysis technique and the fracture-wing method. Secondly, through coupling the reservoir solution and reorientation fracture solution, a semi-analytical solution for multiple reorientation fractures along a horizontal well was derived in the Laplace domain, and its accuracy was also verified. Thirdly, typical flow regimes were identified on the transient-pressure curves. Finally, dimensionless pressure and pressure derivative curves were obtained to analyze the effect of key parameters on the flow behavior, including fracture angle, permeability anisotropy, fracture conductivity, fracture spacing, fracture number, and fracture configuration. Results show that, for an anisotropic rectangular tight reservoir, horizontal wells should be deployed parallel to the direction of principal permeability and fracture reorientation should be controlled to extend along the direction of minimum permeability. Meanwhile, the optimal fracture number should be considered for economic production and the fracture spacing should be optimized to reduce the flow interferences between reorientation fractures. [ABSTRACT FROM AUTHOR]

Background: The aim of this study is to evaluate the effects of recombinant human bone morphogenetic protein 2 (rhBMP-2), human amnion mesenchymal stem cells (hAMSCs), and nanohydroxyapatite/collagen/poly(l-lactide) (nHAC/PLA) in tissue engineering to provide potential approaches for periodontal bone regeneration. Methods: hAMSCs were isolated from discarded amniotic membrane samples and cultured in vitro. Alkaline phosphatase (ALP) staining and alizarin red staining were performed to evaluate the osteoblast (OB) differentiation ability of hAMSCs. Three groups were divided: the experimental group (cells transfected with pcDNA3.1-rhBMP-2), the blank group (cells without gene transfection), and the control group (cells transfected with empty plasmid). RT-PCR and western blot were used to examine whether rhBMP-2 has been successfully expressed. 3-(4,5)-dimethylthiahiazol(-z-y1)-3,5-di-phenytetrazo-liumromide assay (MTT) was done to detect the effect of rhBMP-2 on hAMSCs seeded on nHAC/PLA. ALP activity, mineral formation assay, calcium, phosphate and osteocalcin (OCN) content, and OCN and RUNX2 expression of hAMSCs were detected to evaluate osteogenic differentiation capability of rhBMP-2 on hAMSCs seeded on nHAC/PLA. Results: hAMSCs exhibited intense ALP staining, obvious calcium deposition, and mineralization nodules, and rhBMP-2 were highly expressed in the experimental group. The proliferation of the hAMSCs with rhBMP-2 on nHAC/PLA was significantly higher than the cells without rhBMP-2, and the cells all increased in a time-dependent manner. rhBMP-2 significantly increased the OCN and phosphate content, mineral formation, ALP activity, osteogenic biomarkers OCN, and Runx2, and decreased calcium content in hAMSCs seeded on the nHAC/PLA scaffold. Conclusions: This finding demonstrated that hAMSCs has an ideal OB differentiation ability. rhBMP-2 facilitates the proliferation and osteogenesis of hAMSCs. The nHAC/PLA could act as a good scaffold for hAMSCs seeding, proliferation, and osteogenic differentiation. The application of rhBMP-2, nHAC/PLA, and hAMSCs in tissue engineering may offer promising possibilities for periodontal bone regeneration. [ABSTRACT FROM AUTHOR]

Spontaneous water imbibition is an important mechanism in water-wet fractured reservoirs. For volume-fractured reservoirs, to evaluate the oil productivity and oil recovery through water counter-current imbibition, we propose an analytical method for optimizing the reservoir volume fracturing scheme. Based on the two-phase fluid flow differential equation for capillary force, a three-dimensional water imbibition productivity equation is derived analytically. The equation for the water imbibition productivity considering the fracture network is obtained. A numerical model is constructed to verify the validity of the average capillary diffusivity coefficient and the results of the analytical model. By applying this method to a low permeability reservoir, after volume fracturing and waterflooding huff and puff, the relationship between the tenth year's oil recovery and oil production rate and the length, width, and density of the fracture network is predicted, which gives an optimization of the field fracturing construction scale. The results show that the length and width of the fracture network should be no less than 50% of the well spacing and row spacing to obtain a reasonable production. Considering the fracturing technique and economic feasibility, the higher the density of the fracture network, the better the production obtained. Through hydraulic volume fracturing and waterflooding huff and puff, water imbibition is brought into full play and the 10 year oil recovery is increased by 6%–8% in this area. [ABSTRACT FROM AUTHOR]

Geared toward the problems of predicting the unsteadily changing single oil well production in water flooding reservoir, a machine learning model based on CNN (convolutional neural network) and LSTM (long short-term memory) is established which realizes precise predictions of monthly single-well production. This study is considering more than 60 dynamic and static factors that affect the changes of oil well production, introduce water injection parameters into data set, select 11 main control factors, and then, build a CNN-LSTM model optimized by Bayesian optimization. The effectiveness of the proposed model is verified in a realistic reservoir. The experiment results show that the prediction accuracy of the proposed model is over 90%, which suggests a penitential application in an extensive range of applications. Production forecasting by the developed model is simple, efficient, and accurate, which can provide a guidance for the dynamic analysis of a water flooding reservoir, and work as a good reference of the development and production of other types of reservoirs. [ABSTRACT FROM AUTHOR]

Melanin has an increasing market demand in cosmetics, food, medicine as well as aerospace due to its unique properties. Heterologous expression of 4-hydroxyphenylpyruvate dioxygenase (HPPD) from the melanin-producing strain Streptomyces fungicidicus NW-EN1 in Escherichia coli shortened the fermentation cycle of melanin. HPPD catalyzed 4-hydrophenylpyruvate (HPP) to form homologous acid (HGA) and finally form melanin. The purified melanin had the highest absorption peak at 460 nm. Fourier transform infrared spectroscopy and scanning electron microscope scanning showed that the pigment had universal characteristic peaks. The presence of HGA, a predictor of pyomelanin, was identified by high-performance liquid chromatography analysis. The recombinant E. coli produced 804.4 ± 5.9 mg/L pyomelanin within 48 h. Metal ions had a great influence on the production of pyomelanin. Pyomelanin was stable in response to light intensity and had a protective effect against bacteria under UV irradiation. Meanwhile, we utilized the chromogenic effect after whole-cell catalysis to reflect the inhibition of the HPPD inhibitors (mesotrione and isoxaflutole) on HPPD by observing the color change. As a rapid method to test the action of inhibitors, this method is expected to be useful for the development of HPPD-inhibiting herbicides. [Display omitted] • Engineered strains for melanin production have promising industrial applications. • Enables real-time detection of melanin production. • It provides a new idea for the screening of novel herbicides. [ABSTRACT FROM AUTHOR]

Abstract: NSC-743380 is a novel STAT3 inhibitor that suppresses the growth of several NCI-60 cancer cell lines derived from different tissues and induces regression of xenograft tumors in vivo at various doses. To evaluate the antitumor activity of NSC-743380 in lung cancer cells, we analyzed the susceptibility of 50 NSCLC cell lines to this compound using cell viability assay. About 32% (16 of 50) of these cell lines were highly susceptible to this compound, with a 50% inhibitory concentration (IC50) of <1μM. In mechanistic studies, the increased numbers of apoptotic cells as well as increased PARP cleavage showed that cytotoxic effects correlate with apoptosis induction. Treatment with NSC-743380 inhibited transcription factor STAT3 activation and induced ROS production in sensitive human lung cancer cell lines but not in resistant cells. Blocking ROS generation with the antioxidant NDGA dramatically abolished NSC-743380-induced growth suppression and apoptosis, but had minimal effect on NSC-743380-induced STAT3 inhibition, suggesting that STAT3 inhibition is not caused by ROS production. Interestingly, knockdown of STAT3 with use of shSTAT3 induced ROS generation and suppressed tumor cell growth. Moreover, scavenging ROS induced by STAT3 inhibition also diminished antitumor activity of STAT3 inhibition. In vivo administration of NSC-743380 suppressed tumor growth and p-STAT3 in lung tumors. Our results indicate that NSC-743380 is a potent anticancer agent for lung cancer and that its apoptotic effects in lung cancer cells are mediated by induction of ROS through STAT3 inhibition. [Copyright &y& Elsevier]

Abstract: NSC-741909 (1-[(4-chlorophenyl)methyl]-1H-Indole-3-methanol) is a novel anticancer agent that is highly active against several NCI-60 cancer cell lines. This agent induces sustained activation of mitogen-activated protein kinases (MAPK), including JNK and p38 MAP kinases. However, the mechanisms of its selective antitumor activity in some cancer cell lines remain unknown. We tested the combined effects of NSC-741909 and several kinase inhibitors that target the Raf/MEK/ERK1/2 or PI3K/AKT pathways in two sensitive lung cancer cells. We found that PD98059 (2′-amino-3′-methoxyflavone), a flavone derivative and a selective MEK inhibitor, can dramatically block the cell killing effect of NSC-741909. To determine whether this inhibitory effect is associated with MEK inhibition or other mechanisms, we evaluated the effects of other MEK inhibitors with different chemical structures and flavone derivatives that do not have an effect on MEK. We found that several flavonoids can markedly block NSC-741909-induced apoptosis and JNK activation in a time-dependent manner, regardless of whether they inhibit MEK or not. In contrast, NSC-741909-induced JNK activation and apoptosis were not blocked by other MEK-specific inhibitors U0126 and CI1040. Our results also showed that NSC-741909 induced a dramatic increase of reactive oxygen species in sensitive cells and that flavonoids effectively blocked the NSC-741909-induced reactive oxygen species production which are associated with flavonoids'' antagonistic effects on NSC-741909-induced JNK activation and apoptosis. Those results demonstrated that flavonoids-mediated antagonist effect is through scavenging of reactive oxygen species. Our results may have implication on the design of clinical evaluation of antitumor activity of NSC-741909 or its analogues. [Copyright &y& Elsevier]

We recently found that a small molecule 2[[3-(2,3-dichlorophenoxy)propyl]amino]ethanol (2,3-DCPE) could induce apoptosis and downregulate Bcl-XL expression in various cancer cells. Here, we found that 2,3-DCPE suppressed the proliferation of Bcl-XL-overexpressing cancer cells without inducing apoptosis. Subsequently, we found that 2,3-DCPE could induce S-phase arrest and upregulate p21 but not p27 at a time- and dose-dependent but p53-dispensable manner in DLD-1 human colon cancer cells. Activation of ERK was also detected after treatment with 2,3-DCPE. Moreover, p21 induction was dramatically attenuated by ERK inhibitors PD98059 and U0126. Induction of p21 and S-phase arrest and corresponding activation of ERK were also observed in ATM-defective cells, suggesting that 2,3-DCPE-induced these events were ATM-dispensable. Furthermore, ERK inhibitors dramatically attenuated 2,3-DCPE-induced S-phase arrest. Together, our data indicate that ERK activation correlated with the 2,3-DCPE-mediated induction of p21 expression and S-phase arrest. This finding may have implication for cancer therapy.Oncogene (2004) 23, 4984-4992. doi:10.1038/sj.onc.1207645 Published online 3 May 2004 [ABSTRACT FROM AUTHOR]

Regulatory T cells are a subgroup of T cells with immunomodulatory functions. Different from most cytotoxic T cells and helper T cells, they play a supporting role in the immune system. What's more, regulatory T cells often play an immunosuppressive role, which mainly plays a role in maintaining the stability of the immune system and regulating the immune response in the body. However, recent studies have shown that not only playing a role in autoimmune diseases, organ transplantation, and other aspects, regulatory T cells can also play a role in the immune escape of tumors in the body, through various mechanisms to help tumor cells escape from the demic immune system, weakening the anti-cancer effect in the body. For a better understanding of the role that regulatory T cells can play in cancer, and to be able to use regulatory T cells for tumor immunotherapy more quickly. This review focuses on the research progress of various mechanisms of regulatory T cells in the tumor environment, the related research of tumor cells acting on regulatory T cells, and the existing various therapeutic methods acting on regulatory T cells. • Unlike in the past, Treg cells have also been found to play a powerful role in cancer treatment. • Treg cells exert immunosuppressive effects through various ways, such as cell-cell contact, secretion of cytokines, regulation of DC function, binding to chemokine CCL22/CCL17, and so on, and acting in the tumor microenvironment. • Tumorigenesis is often accompanied by an increase in the number of Treg cells. • Many recent studies have found that metabolic pathways, receptors, and proteins on Treg cells, bile acids, and even apoptotic Treg cells can promote Treg cells to exert immune suppression, and then help tumors escape from the immune system. • More and more targeted therapy drugs that block the target sites on Treg cells and destroy the homeostasis between Th17 cells and Treg cells can be effective immunotherapy for tumors. [ABSTRACT FROM AUTHOR]

Reducing carbon emissions and increasing carbon sinks are key strategies to effectively remove greenhouse gases from the atmosphere. Assessing the current carbon emission status and predicting future carbon emission scenarios could help formulate effective regional carbon emission reduction targets. However, it is necessary to enhance the carbon sink capacity of terrestrial ecosystems and improve forest management methods to promote greenhouse gas absorption. In this study, the spatiotemporal characteristics and dynamic evolution of fossil fuel CO 2 (FFCO 2) emissions in China from 2000 to 2019 were analyzed using the standard deviation ellipse, kernel density of emissions, and Theil index. A backpropagation (BP) neural network optimized with a genetic algorithm (GA) was used to predict FFCO 2 emission during 2020–2030. The biomass increment methodology was used to predict the potential carbon sinks generated by Chinese Certified Emission Reduction (CCER) carbon-sink forestry projects during 2020–2030. The results showed that China's FFCO 2 emissions exhibited a gradual increasing trend during 2000–2019, with an average annual growth rate of 6.29%. China's FFCO 2 emissions show a greater distribution on the southeastern coast than in the northwestern interior. The GA-BP prediction shows that China's FFCO 2 emissions will continue to fluctuate and increase between 2020 and 2030. The potential of carbon sinks will be 0.69 × 108 Mg C generated by the CCER carbon-sink forestry projects during 2020–2030, which could offset 0.56% of FFCO 2 emissions. In the future, imbalances in regional development should be considered when formulating carbon-reduction strategies. Moreover, using carbon-sink of forestry projects of CCER to balance economic development including poverty eradication and environmental conservation should be considered. Specifically, establishing a methodology of projects for the management of natural forests' carbon-sink will be an important future strategy. • China's FFCO 2 emissions rose in volatility with an average growth rate of 6.29%. • The spatial differences of FFCO 2 emissions are gradually narrowing. • FFCO 2 emissions will continue to rise in the future. • Carbon-sink forestry project is ideal approach to offset carbon emission. • The Methodology of Forests Management for natural forest should be focused. [ABSTRACT FROM AUTHOR]

Predictive analysis of the reservoir surveillance data is crucial for the high-efficiency management of oil and gas reservoirs. Here we introduce a new approach to reservoir surveillance that uses the machine learning tree boosting method to forecast production data. In this method, the prediction target is the decline rate of oil production at a given time for one well in the low-permeability carbonate reservoir. The input data to train the model includes reservoir production data (e.g., oil rate, water cut, gas oil ratio (GOR)) and reservoir operation data (e.g., history of choke size and shut-down activity) of 91 producers in this reservoir for the last 20 years. The tree boosting algorithm aims to quantitatively uncover the complicated hidden patterns between the target prediction parameter and other monitored data of a high variety, through state-of-the-art automatic classification and multiple linear regression algorithms. We also introduce a segmentation technique that divides the multivariate time-series production and operation data into a sequence of discrete segments. This feature extraction technique can transfer key features, based on expert knowledge derived from the in-reservoir surveillance, into a data form that is suitable for the machine learning algorithm. Compared with traditional methods, the approach proposed in this article can handle surveillance data in a multivariate time-series form with different strengths of internal correlation. It also provides capabilities for data obtained in multiple wells, measured from multiple sources, as well as of multiple attributes. Our application results indicate that this approach is quite promising in capturing the complicated patterns between the target variable and several other explanatory variables, and thus in predicting the daily oil production rate. [ABSTRACT FROM AUTHOR]

• Concurrent aspirin use with osimertinib in EGFR -mutant NSCLC patients was associated with improved PFS. • The benefit is independent of lines of therapy, CNS metastasis, EGFR mutation type, TP53 status, PD-L1 status, age or gender. • With aspirin use, the progression-free survival in L858R patients are similar to the EGFR 19Del patients. Osimertinib is the treatment of choice for advanced EGFR -mutant non-small cell lung cancer (NSCLC). However, novel strategies to improve the duration of disease control are still urgently needed. Aspirin has been shown to decrease cancer incidence and improve outcomes in various malignancies. Therefore, we evaluated a cohort of patients who received osimertinib with or without concurrent use of aspirin to assess whether the addition of aspirin may lead to improved clinical outcomes. MD Anderson Cancer Center GEMINI database was retrospectively queried for EGFR -mutant NSCLC patients who received osimertinib with or without concurrent use of aspirin for progression-free survival (PFS) and overall survival (OS). A total of 365 patients were identified including 77 which had concurrent use of aspirin. Patients in the aspirin-osimertinib group had significantly improved PFS (21.3 vs 11.6 months; HR, 0.52; 95 % CI, 0.38−0.70) and OS (Not reached vs 32.3 months; HR, 0.56; 95 % CI, 0.35−0.91) compared to osimertinib group. In subgroup analyses, the aspirin-associated PFS benefit was observed in patients with and without central nervous system (CNS) metastases, as well as in osimertinib first-line setting and in subsequent line setting. The median PFS in EGFR 19Del patients was longer than EGFR L858R patients with osimertinib, and when aspirin was added, the median PFS significantly improved in both groups regardless of lines of therapy. The benefit from aspirin was independent of age, gender, TP53 mutational status, or PD-L1 positivity. Concurrent aspirin use with osimertinib in EGFR -mutant NSCLC patients was associated with improved survival, regardless of lines of therapy, CNS metastatic status, EGFR mutation type, age, gender, TP53 , and PD-L1 status. [ABSTRACT FROM AUTHOR]

Mast cells (MCs) are the major effector cells of allergic rhinitis (AR). The present study aimed to investigate the effects of C-C chemokine receptor type 3 (CCR3) on the proliferation, apoptosis, chemotaxis and activated degranulation of mouse MCs. Mouse bone marrow-derived MCs were cultured in vitro, purified and identified using toluidine blue staining and flow cytometry. Three different CCR3-short hairpin (shRNA) lentiviral vectors were constructed and transfected into MCs, and the mRNA and protein expression levels of CCR3 were assessed by reverse transcription-quantitative PCR and western blotting. Proliferation and apoptosis of the MCs were measured using Cell Counting kit-8 (CCK-8) assays and flow cytometry, respectively. MC chemotaxis was assessed by Transwell assay and quantified using flow cytometry. The activation of MC degranulation was examined using ELISAs. The results demonstrated that MCs were appropriately isolated, and identified that CCR3-shRNA2 presented the higher knockdown effect among the three shRNAs tested. Following 96 h of transfection, the results of CCK-8 and flow cytometry assays demonstrated that CCR3-shRNA2 inhibited MC proliferation and promoted MC apoptosis. The results from the Transwell assay indicated that CCR3-shRNA2 restrained MC chemotaxis, whereas ELISA results demonstrated that CCR3-shRNA2 suppressed MC degranulation. In conclusion, CCR3-shRNA2 effectively downregulated CCR3 mRNA and protein expression levels in mouse MCs. In addition, CCR3-shRNA2 promoted MC apoptosis and suppressed the proliferation, chemotaxis and degranulation of mouse MCs, suggesting that CCR3-shRNA2 may serve as a therapeutic tool for the treatment of allergic rhinitis. [ABSTRACT FROM AUTHOR]

The Yinggen‐Ejinaqi Basin (YEB) is located in the central‐southern part of the Central Asian Orogenic Belt (CAOB). Tectonically, the basin is situated at the intersection between the eastern and western CAOB, where Late Palaeozoic strata were well exposed. Hence, it offers a great opportunity to study the deep strata of the eastern CAOB. In this paper, based on extensive studies of Upper Palaeozoic field outcrops and reanalysis of associated geochemical and geochronological data in previous research, the local stratigraphic correlation is established, and the tectonic evolution, sedimentary filling, sedimentary characteristics, and petroleum system of the YEB are discussed. It is revealed that: (a) The filling characteristics of the Upper Palaeozoic strata in YEB are closely related to the closure of the Paleo‐Asian Ocean (PAO). YEB underwent subduction‐related compression during the initial extensional phase of the fore‐arc basin from the Viséan to the Serpukhovian (late Early Carboniferous). During the Bashkirian–Sakmarian interval (Late Carboniferous to Early Permian), it was in subduction‐related fore‐arc and postarc rifting phases. During the Artinskian–Capitanian (Early‐Middle Permian) times, it was in an intracontinental rifting‐depression phase. During the Wuchapingian (Late Permian), it was in an intracontinental compressional phase. Tectonostratigraphy, tectonic evolution, and hydrocarbon potential assessments of the study area show that the Zhusileng Hangwula‐Tost Ul tectonic zone (ZHTUTZ) and southwestern part of Querrshan‐Atasbogd tectonic zone (QATZ) are identified as the main prospective areas for the exploration in the YEB. (b) According to the tectonostratigraphic analysis, tectonic evolution and hydrocarbon system of Carboniferous–Permian in the YEB, the YEB has similar attributes to the basin province in western CAOB (e.g., Santanghu and Junggar basins) and eastern CAOB (Erlian, Songliao Basin). To explore commercial oil and gas in the deeper strata (Carboniferous–Permian) of the eastern CAOB basins, further tectonostratigraphic analyses and comprehensive assessment on hydrocarbon potentials are necessitated in the near future. [ABSTRACT FROM AUTHOR]

Background: Patient-derived xenograft (PDX) models increasingly are used in translational research. However, the engraftment rates of patient tumor samples in immunodeficient mice to PDX models vary greatly.Methods: Tumor tissue samples from 308 patients with non-small cell lung cancer were implanted in immunodeficient mice. The patients were followed for 1.5 to approximately 6 years. The authors performed histological analysis of PDXs and some residual tumor tissues in mice with failed PDX growth at 1 year after implantation. Quantitative polymerase chain reaction and enzyme-linked immunoadsorbent assay were performed to measure the levels of Epstein-Barr virus genes and human immunoglobulin G in PDX samples. Patient characteristics were compared for PDX growth and overall survival as outcomes using Cox regression analyses. Disease staging was based on the 7th TNM staging system.Results: The overall engraftment rate for PDXs from patients with non-small cell lung cancer was 34%. Squamous cell carcinomas had a higher engraftment rate (53%) compared with adenocarcinomas. Tumor samples from patients with stage II and stage III disease and from larger tumors were found to have relatively high engraftment rates. Patients whose tumors successfully engrafted had worse overall survival, particularly those individuals with adenocarcinoma, stage III or stage IV disease, and moderately differentiated tumors. Lymphoma formation was one of the factors associated with engraftment failure. Human CD8-positive and CD20-positive cells were detected in residual samples of tumor tissue that failed to generate a PDX at 1 year after implantation. Human immunoglobulin G was detected in the plasma of mice that did not have PDX growth at 14 months after implantation.Conclusions: The results of the current study indicate that the characteristics of cancer cells and the tumor immune microenvironment in primary tumors both can affect engraftment of a primary tumor sample. [ABSTRACT FROM AUTHOR]

Many oil wells in closed reservoirs continue to produce in the pseudo-steady-state flow regime for a long time. The principal objective of this work is to investigate the characteristics of two key pseudo-steady-state parameters—pseudo-steady-state constant (bDpss) and pseudo-skin factor (S)—for a well penetrated by a fracture with an azimuth angle (θ) in an anisotropic reservoir. Firstly, a general analytical pressure solution for a finite-conductivity fracture with or without an azimuth angle in an anisotropic rectangular reservoir was developed by using the point-source function and spatial integral method, and two typical cases were employed to verify this solution. Secondly, with the asymptotic analysis method, the expressions of pseudo-steady-state constant and pseudo-skin factor were obtained on the basis of their definitions, and the effects of permeability anisotropy, fracture azimuth angle, fracture conductivity and reservoir shape on them were discussed in detail. Results show that all the bDpss-θ and S-θ curves are symmetric around the vertical line, θ = 90° and form a hump or groove shape. The optimized fracture direction in an anisotropic reservoir is perpendicular to the principal permeability axis. Furthermore, a new formula to calculate pseudo-skin factor was successfully proposed based on these two parameters' relationship. Finally, as an application of pseudo-steady-state constant, a set of Blasingame format rate decline curves for the proposed model were established. [ABSTRACT FROM AUTHOR]

The effects of grazing on the soil carbon of an alpine meadow on the Qinghai-Tibetan Plateau were studied. The aims were to estimate the effects of grazing on the spatial and vertical distribution of soil organic carbon, estimate the potential carbon sink and provide suggestions for sustainable grassland management. Biomass and soil characteristics of the topmost 1 m soil layer in plots under three different grazing intensities were investigated. Soil organic carbon density (SOCD) and stocks (SOCS) were calculated as weighted averages. Soil organic carbon content (SOCC) decreased with increasing grazing intensity and soil depth, with the highest values observed in the top 30 cm of the soil layer at light grazing (LG) sites. Soil water content, total carbon, and biomass had a positive relationship with SOCC. However, bulk density was negatively correlated with SOCC. The lowest SOCD and SOCS were in the 30–100 cm soil layer at heavy grazing (HG) sites, indicating that HG could have significant negative effects on SOC. It could take at least ∼60 years for C stocks at HG sites to reach a steady state. A regime of low grazing is recommended for combining C sequestration with sustainable development. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate the effects of C-C chemokine receptor type 3 (CCR3) gene knockout on allergic rhinitis (AR) in mice, as well as the underlying molecular mechanisms. Ovalbumin was administrated to CCR3+/+ and CCR3−/− BALB/c mice to establish an AR model. The mice were divided into four groups: i) Normal control (CG), ii) AR model (AR), iii) CCR3 knockout CG (CCR3−/−CG) and iv) AR model with CCR3 knockout (CCR3−/−AR). Histological sections of nasal mucosae were examined by hematoxylin and eosin staining, which revealed that CCR3 knockout suppressed the invasion of inflammatory cells and relieved the damage of nasal mucosae. Peripheral blood smear and nasal-washing smears were evaluated by Wright's staining. Eosinophil (EOS) numbers in nasal mucosae, peripheral blood, and nasal washings of the various groups were ranked in the order: AR>CCR3−/−AR>CG>CCR3−/−. mRNA expression levels of CCR3, EOS peroxidase (EPO), EOS cationic protein (ECP), and major basic protein (MBP) in the peripheral serum and nasal washings were detected by reverse transcription-polymerase chain reaction. Interferon-γ (IFN-γ), interleukin (IL)-4, IL-10, and immunoglobulin E (IgE) protein levels in the peripheral serum and nasal washings were investigated by ELISA. CCR3 mRNA expression was not detected in the CCR3−/− and CCR3−/−AR groups, whereas expression levels in the AR group were markedly higher compared with expression in the CG group. Compared with the CG-associated groups (i.e., the CG and CCR3−/−CG groups), the levels of EPO, ECP, MBP, IL-4, and IgE were significantly increased in the AR-associated groups (that is, R and CCR3−/−AR). In addition, the CCR3−/−AR group mice produced significantly lower levels of EPO, ECP, MBP, IL-4 and IgE compared with the AR group, whereas the expression levels of IFN-γ and IL-10 were increased. CCR3 gene knockout may alleviate EOS invasion and the inflammatory response in AR model mice by reducing the expression levels of EPO, ECP, MBP, IL-4, and IgE, and increasing the expression of IL-10 and IFN-γ. [ABSTRACT FROM AUTHOR]

The electrochemical N 2 reduction reaction (NRR) is greatly challenged by relatively low faradaic efficiency (FE) owing to fierce competition from the H 2 evolution reaction (HER) suffered by the current transition-metal electrocatalysts (d -block elements). Considering the unique electronic structure of group-VA pnictogens (p -block elements) that is complementary to d -block elements in HER suppression, we report a conceptually new Janus electrocatalyst to tackle the selectivity challenge. Specifically, an amorphous NiSb 2 O 6– x nanofiber is synthesized, in which Ni and Sb contribute to a synergistic catalysis pathway for inhibiting the two-electron transfer process of HER as well as activating the adsorbed N 2 molecules. Moreover, amorphization is able to produce more oxygen vacancies, thus mimicking the "π back-donation" process to promote the NRR performance. Benefiting from this coupled element design and amorphization strategy, the amorphous NiSb 2 O 6– x nanofiber significantly outperforms either component (NiO or Sb 2 O 4) as well as its crystalline counterparts in terms of NH 3 yield and FE. [Display omitted] • A d -/ p -block Janus electrocatalyst, i.e. , amorphous NiSb 2 O 6– x nanofiber is synthesized. • Within the Ni–Sb active center, Ni and Sb are responsible for N 2 activation and HER suppression. • Amorphization produces more oxygen vacancies to mimic the "π back-donation" process. • Amorphous NiSb 2 O 6– x nanofiber outperforms its crystalline counterparts in terms of NH 3 yield and FE. • DFT simulations reveal a -NiSb 2 O 6– x is more liable for N 2 adsorption and activation as well as NH 3 release. [ABSTRACT FROM AUTHOR]

Molecular annotated patient-derived xenograft (PDX) models are useful for the preclinical investigation of anticancer drugs and individualized anticancer therapy. We established 23 PDXs from 88 surgical specimens of lung cancer patients and determined gene mutations in these PDXs and their paired primary tumors by ultradeep exome sequencing on 202 cancer-related genes. The numbers of primary tumors with deleterious mutations in TP53, KRAS, PI3KCA, ALK, STK11, and EGFR were 43.5%, 21.7%, 17.4%, 17.4%, 13.0%, and 8.7%, respectively. Other genes with deleterious mutations in ≥3 (13.0%) primary tumors were MLL3, SETD2, ATM, ARID1A, CRIPAK, HGF, BAI3, EP300, KDR, PDGRRA and RUNX1 . Of 315 mutations detected in the primary tumors, 293 (93%) were also detected in their corresponding PDXs, indicating that PDXs have the capacity to recapitulate the mutations in primary tumors. Nevertheless, a substantial number of mutations had higher allele frequencies in the PDXs than in the primary tumors, or were not detectable in the primary tumor, suggesting the possibility of tumor cell enrichment in PDXs or heterogeneity in the primary tumors. The molecularly annotated PDXs generated from this study could be useful for future translational studies. [ABSTRACT FROM AUTHOR]

Simple Summary: Siberian musk deer (Moschus moschiferus L.) populations and their habitat decreased significantly over the past decades due to unsustainable, long-term hunting and deforestation. To support the species' conservation, we assessed its potential distribution, conservation priority areas, core patch fragmentation, and potential connectivity corridors in Northeast China. We concluded that large areas of a high-quality M. moschiferus habitat with low fragmentation and low human influence remain in the northern Greater Khingan Mountains. In contrast, a habitat in the Lesser Khingan Mountains and the Changbai Mountains was highly fragmented and highly influenced by human activity. The Greater Khingan Mountains offer a suitable habitat for the recovery of M. moschiferus populations in Northeast China. These findings offer recommendations to support the Chinese government's goal of establishing protected area systems with national parks in Northeast China. Species conservation actions are guided by available information on the biogeography of the protected species. In this study, we integrated the occurrence data of Siberian musk deer (Moschusmoschiferus L.) collected from 2019 to 2021 with species distribution models to estimate the species' potential distribution in Northeast China. We then identified conservation priority areas using a core-area zonation algorithm. In addition, we analyzed core patch fragmentation using FRAGSTATS. Lastly, we identified potential connectivity corridors and constructed a potential protection network based on the least-cost path and the circuit theory. The results showed concentrations of M. moschiferus in the northern Greater Khingan Mountains, the southeastern Lesser Khingan Mountains, and the eastern Changbai Mountains, with a potential distribution area of 127,442.14 km2. Conservation priority areas included 41 core patches with an area of 106,306.43 km2. Patch fragmentation mainly occurred in the Changbai Mountains and the Lesser Khingan Mountains. We constructed an ecological network composed of 41 core patches and 69 linkages for M. moschiferus in Northeast China. The results suggest that the Greater Khingan Mountains represent the most suitable area to maintain the stability of M. moschiferus populations in Northeast China. Considering the high habitat quality requirements of M. moschiferus and its endangered status, we propose that the Chinese government accelerates the construction of the Greater Khingan Mountains National Park and the Lesser Khingan Mountains National Park and enlarges the Northeast China Tiger and Leopard National Park to address the fragmentation of protected areas and the habitat of M. moschiferus. [ABSTRACT FROM AUTHOR]

Transition metal oxalates have attracted people's attention owing to their low cost, low lithium insertion potential and high theoretical reversible capacities. Disappointingly, high irreversible capacity thanks to the formation of SEI as well as the consumption and exfoliation of active materials during the process of cycling severely restrict its application of it. In this work, a comprehensive evaluation of Co, Ni, Cu and Zn doped manganese oxalate was made. All samples are synthesized via facile and time-saving microwave hydrothermal method. It is intriguing that merely 30 ​min is required to accomplish the entire process and all samples possess fine electrochemical performance. As far as the four bimetallic oxalates, the resulting Mn 0·5 Ni 0·5 C 2 O 4 exhibits the optimum performance (746.2 ​mA ​h ​g−1 after 100 cycles at 0.2 ​A ​g−1 and 546.7 ​mA ​h ​g−1 at 1 ​A ​g−1 after 400 cycles), which can be attributed to one-dimensional rod-like morphology of Mn 0·5 Ni 0·5 C 2 O 4 as well as the synergistic and catalytic effect of Mn and Ni, resulting in faster electrode kinetics. Mn 0.5 Ni 0.5 C 2 O 4 displays incalculable potential and can be applied in the highly reversible lithium-ion batteries. [Display omitted] • A comprehensive evaluation of multiple metal doped manganese oxalate for lithium storage. • The well-defined one-dimensional nanorod-like structure has a large specific area of 69.5 ​m2 ​g−1. • The resulting Mn 0·5 Ni 0·5 C 2 O 4 exhibits the optimum performance, which outperforms most binary oxalates. [ABSTRACT FROM AUTHOR]

• In this study, we revealed that the TP53INP1 expression was was inversely associated with miR-155-5p in ILC2s. • MiR-155-5p disrupted the Th1/Th2 cytokines expression balance and suppressed the apoptosis of ILC2s via targeting TP53INP1 in AR. • TP53INP1 might exert its anti-inflammatory roles via inhibition NF-κB signaling pathway in AR. • Taken together, these findings suggested that miR-155-5p aggravated the inflammatory response of AR dominated by ILC2s via targeting TP53INP1, which may aid in the development of novel therapeutic agents for AR. As a key component of innate immunity, group 2 innate lymphoid cells (ILC2s) play a key role in Allergic rhinitis (AR). We previously demonstrated that both miR-155-5p and ILC2s are overexpressed in the nasal mucosa of AR patients, but the underlying mechanism remains unclear. At present study, we revealed that miR-155-5p was highly expressed in ILC2s of AR patients. Moreover, miR-155-5p promoted the secretion of Th2 cytokines of ILC2s, while inhibited the secretion of Th1 cytokines and the apoptosis of ILC2s. Meanwhile, the TP53INP1 expression was poorly expressed in ILC2s of AR patients. A dual luciferase reporter assay demonstrated that TP53INP1 was a direct target of miR-155-5p, and its expression was inversely associated with miR-155-5p in ILC2s. Furthermore, TP53INP1 inhibited the secretion of Th2 cytokines of ILC2s, while promoted the secretion of Th1 cytokines and the apoptosis of ILC2s. Notably, rescue experiments demonstrated that overexpression of TP53INP1 could partially reverse the effect of miR-155-5p on ILC2s. Taken together, these findings suggested that miR-155-5p aggravated the inflammatory response of AR dominated by ILC2s via targeting TP53INP1, which may aid in the development of novel therapeutic agents for AR. [ABSTRACT FROM AUTHOR]

• Increased SNHG8 expression in nasopharyngeal carcinoma. • SNHG8 promotes nasopharyngeal carcinoma progression in vitro and in vivo. • miR-656−3p/SATB1 was the effector molecules of SNHG8. Long non-coding RNA (lncRNA) has been proposed to regulate tumorigenesis, however, the role of small nucleolar RNA host gene 8 (SNHG8) in nasopharyngeal carcinoma (NPC) remains unclear. Levels of SNHG8 in NPC tissues and cells were analyzed with real‐time quantitative PCR method. Cell counting kit-8 assay, colony formation assay, wound-healing assay, and transwell invasion assay were performed to detect cell viability, migration, and invasion. Luciferase activity assay and RIP assay were performed to explore relationships among SNHG8, microRNA-656−3p (miR-656−3p), and special AT-rich sequence-binding protein 1 (SATB1). We found SNHG8 level was increased expression in NPC tissues and cells. In vitro assays revealed that SNHG8 stimulates NPC cell proliferation, colony formation, cell migration, and cell invasion. In vivo assay confirmed knockdown of SNHG8 could hamper tumor growth. Furthermore, we showed SNHG8 serves as a sponge for miR-656−3p to regulate SATB1 expression, and participated in NPC progression. In summary, our work indicated the importance of SNHG8 in NPC progression, which provided novel treatment methods for NPC. [ABSTRACT FROM AUTHOR]

With the gradual liberalization of the energy market, the future integrated energy system will be composed of multiple agents. Therefore, this paper proposes an optimization dispatch method considering energy hub technology and multi-agent interest balance in an integrated energy system. Firstly, an integrated energy system, including equipment for cogeneration, renewable energy, and electric vehicles, is established. Secondly, energy hub technologies, such as demand response, electricity storage, and thermal storage, are comprehensively considered, and the integrated energy system is divided into three agents: Integrated energy service providers, renewable energy owners, and users, respectively. Then, with the goal of balancing the interests of each agent, the model is solved by the non-dominated sorting genetic algorithm-III (NSGA-III) to obtain the Pareto frontier. Since the Pareto frontier is a series of values, the optimal solution of each agent in the Pareto frontier is found by the technical for order preference with a similar to ideal solution (TOPSIS). Ultimately, taking an integrated energy demonstration park in China as a case study, the function of energy hub technology is analyzed by simulation, and the proposed method is verified to be effective and practicable. [ABSTRACT FROM AUTHOR]

Background: Because patient-derived xenografts (PDXs) are grown in immunodeficient mouse strains, PDXs are regarded as lacking an immune microenvironment. However, whether patients' immune cells co-exist in PDXs remains uncharacterized.Methods: We cultured small pieces of lung PDX tissue in media containing human interleukin-2 and characterized the proliferated lymphocytes by flow cytometric assays with antibodies specific for human immune cell surface markers. Presence of immune cells in PDXs was also determined by immunohistochemical staining.Results: Human tumor-infiltrating lymphocytes (TILs) were cultured from nine of 25 PDX samples (36%). The mean time of PDX growth in immunodeficient mice before obtaining TILs in culture was 113 days (range 63-292 days). The TILs detected in PDXs were predominantly human CD8+ T cells, CD4+ T cells, or CD19+ B cells, depending on cases. DNA fingerprint analysis showed that the TILs originated from the same patients as the PDXs. Further analysis of two PDX-derived CD8+ T cells showed that they were PD-1-, CD45RO+, and either CD62L+ or CD62L-, suggesting they were likely memory T cells. Immunohistochemical staining showed that human T cells (CD8+ or CD4+), B cells (CD19+), and macrophages (CD68+) were present in stroma or intraepithelial cancer structures and that human PD-L1 was expressed in stromal cells. Moreover, the patient-derived immune cells in PDX can be passaged to the F2 generation and may migrate to spleens of PDX-bearing mice.Conclusions: Patient-derived immune cells co-exist in early passages of PDXs in some lung cancer PDX models. The CD8+ cells from PDXs were likely memory T cells. These results suggest that PDXs can be used for evaluating the functionality of immune components in tumor microenvironments. [ABSTRACT FROM AUTHOR]

Anti-PD-1 and anti-PD-L1 immunotherapy has provided a new therapeutic opportunity for treatment of advanced-stage non-small cell lung cancer (NSCLC). However, overall objective response rates are approximately 15%–25% in all NSCLC patients who receive anti-PD therapy. Therefore, strategies to overcome primary resistance to anti-PD immunotherapy are urgently needed. We hypothesized that the barrier to the success of anti-PD therapy in most NSCLC patients can be overcome by stimulating the lymphocyte infiltration at cancer sites through locoregional virotherapy. To this end, in this study, we determined combination effects of anti-PD immunotherapy and oncolytic adenoviral vector-mediated tumor necrosis factor-α-related apoptosis-inducing ligand (TRAIL) gene therapy (Ad/E1-TRAIL) or adenoviral-mediated TP53 (Ad/CMV-TP53) gene therapy in syngeneic mice bearing subcutaneous tumors derived from M109 lung cancer cells. Both anti–PD-1 and anti–PD-L1 antibodies failed to elicit obvious therapeutic effects in the M109 tumors. Intratumoral administration of Ad/E1-TRAIL or Ad/CMV-TP53 alone suppressed tumor growth in animals preexposed to an adenovector and bearing subcutaneous tumors derived from M109 cells. However, combining either anti–PD-1 or anti–PD-L1 antibody with these two adenoviral vectors elicited the strongest anticancer activity in mice with existing immunity to adenoviral vectors. Dramatically enhanced intratumoral immune response was detected in this group of combination therapy based on infiltrations of CD4+ and CD8+ lymphocytes and macrophages in tumors. Our results demonstrate that resistance to anti–PD-1 immunotherapy in syngeneic mouse lung cancer can be overcome by locoregional virotherapy. [ABSTRACT FROM PUBLISHER]

Ibrutinib, which irreversibly inhibits Bruton tyrosine kinase, was evaluated for antitumor activity in a panel of non-small cell lung cancer (NSCLC) cell lines and found to selectively inhibit growth of NSCLC cells carrying mutations in the epidermal growth factor receptor (EGFR) gene, including T790M mutant and erlotinib-resistant H1975 cells. Ibrutinib induced dose-dependent inhibition of phosphor-EGFR at both Y1068 and Y1173 sites, suggesting ibrutinib functions as an EGFR inhibitor. Survival was analyzed by Kaplan-Meier estimation and log-rank test. All statistical tests were two-sided. In vivo study showed that ibrutinib statistically significantly suppressed H1975 tumor growth and prolonged survival of the tumor bearing mice (n = 5 per group). The mean survival times for solvent- and erlotinib-treated mice were both 17.8 days (95% confidence interval [CI] = 14.3 to 21.3 days), while the mean survival time for ibrutinib-treated mice was 29.8 days (95% CI = 26.0 to 33.6 days, P = .008). Our results indicate that ibrutinib could be a candidate drug for treatment of EGFR-mutant NSCLC, including erlotinib-resistant tumors. [ABSTRACT FROM AUTHOR]

Ibrutinib, which irreversibly inhibits Bruton tyrosine kinase, was evaluated for antitumor activity in a panel of non–small cell lung cancer (NSCLC) cell lines and found to selectively inhibit growth of NSCLC cells carrying mutations in the epidermal growth factor receptor (EGFR) gene, including T790M mutant and erlotinib-resistant H1975 cells. Ibrutinib induced dose-dependent inhibition of phosphor-EGFR at both Y1068 and Y1173 sites, suggesting ibrutinib functions as an EGFR inhibitor. Survival was analyzed by Kaplan–Meier estimation and log-rank test. All statistical tests were two-sided. In vivo study showed that ibrutinib statistically significantly suppressed H1975 tumor growth and prolonged survival of the tumor bearing mice (n = 5 per group). The mean survival times for solvent- and erlotinib-treated mice were both 17.8 days (95% confidence interval [CI] = 14.3 to 21.3 days), while the mean survival time for ibrutinib-treated mice was 29.8 days (95% CI = 26.0 to 33.6 days, P = .008). Our results indicate that ibrutinib could be a candidate drug for treatment of EGFR-mutant NSCLC, including erlotinib-resistant tumors. [ABSTRACT FROM PUBLISHER]

Background:We recently showed that IGFBP2 is overexpressed in primary lung cancer tissues. This study aims to determine whether IGFBP2 is elevated in blood samples of lung cancer patients and whether its level is associated with clinical outcomes. Methodology/Principal Findings:Plasma IGFBP2 levels were determined blindly by enzyme-linked immunosorbent assay in 80 lung cancer patients and 80 case-matched healthy controls for comparison. We analyzed blood samples for IGFBP2 levels from an additional 84 patients with lung cancer and then tested for associations between blood IGFBP2 levels and clinical parameters in all 164 lung cancer patients. All statistical tests were two-sided and differences with p<0.05 were considered significant. The mean plasma concentration of IGFBP2 in lung cancer patients was significantly higher than that in healthy controls (388.12±261.00 ng/ml vs 219.30±172.84 ng/ml, p<0.001). IGFBP2 was increased in all types of lung cancer, including adenocarcinoma, squamous cell cancer, and small-cell cancer, regardless of patients’ age, sex, or smoking status. IGFBP2 levels were mildly but significantly associated with tumor size and were significantly higher in stage IV than stage I or III disease. A multivariate analysis showed that lung cancer patients whose blood IGFBP2 was higher than 160.9 ng/ml had a poor survival outcome, with a hazard ratio of 8.76 (95% CI 1.12-68.34, p=0.038 after adjustment for tumor size, pathology, and stage). The median survival time for patients with blood IGFBP2 >160.9 ng/ml is 15.1 months; whereas median survival time was 128.2 months for the patients whose blood IGFBP2 was ≤160.9 ng/ml (p =0.0002). Conclusions/Significance:Blood IGFBP2 is significantly increased in lung cancer patients. A high circulating level of IGFBP2 is significantly associated with poor survival, suggesting that blood IGFBP2 levels could be a prognostic biomarker for lung cancer. [ABSTRACT FROM AUTHOR]