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Objective With the continuous advancement of aging in China, the number of older inpatients has increased sharply. Older patients have a high demand for planning their discharge services. Nurses serve as the leader of discharge planning for patients; there is a lack of reliable evaluation tool to evaluate the core competitiveness of nurses who implement discharge planning for older patients in China. The purpose of this study was to validate the index for the core competence of nurses who lead discharge planning for older patients developed by a project team through the Delphi method in the early stage. Methods A cross-sectional questionnaire survey with 3-stage stratified sampling was used to select 1075 nurses from 17 public general hospitals in Ningxia, China. Results The index consists of 4 first-level indicators, 13 second-level indicators, and 57 third-level indicators. The results show that 57 third-level indicators had good discrimination. With exploratory factor analysis (EFA), 4 common factors that explained 72.79% of the total variance were extracted. The Cronbach’s α was 0.98, and the retest reliability within a 14-d interval was 0.86. The confirmatory factor analysis (CFA) results show that the fit of the index structure was good. The criterion validity was 0.73. Conclusions The index presented excellent psychometric properties and can be used to measure the core competence of nurses in implementing discharge planning for older patients in China.

Purpose Tacrolimus is a potent immunosuppressant extensively, due to different gene expressions of CYP3A5 in different populations, tacrolimus has a narrow therapeutic index and there is significant heterogeneity in the dose required to achieve target blood concentrations, leading to difficulty in determining the optimal initial dosage. Methods 145 Chinese renal transplant recipients were divided into two groups according to different CYP3A5 genotypes. The initial oral dose of tacrolimus for patients with CYP3A5*1/*3 and *1/*1 genotypes (expressers) was 0.14 to 0.18 mg/kg/day, and 0.08 to 0.1 mg/kg/day for that with CYP3A5*3/*3 genotypes (non-expressing type). The primary endpoints were the time to achieve the first target tacrolimus blood concentration (TBC) (7 ~ 13 ng/ml) and the proportion of patients reaching this target range on Day 3 ~ 7. Secondary endpoints were the mean doses of tacrolimus, acute rejection, and delayed renal allograft function of tacrolimus. Results The time needed to achieve the first target TBC after transplantation is as follows: expressers patients (N = 59) at 7 days (3 to 28) and non-expressers patients (N = 86) at 3 days (3 to 14) (P

With the continuous development of science and technology, the information age has arrived, and people have fully entered the information age. In this new era, Internet technology has achieved unprecedented development, and many innovative technologies have also been proposed. The competition in the logistics industry is becoming more and more fierce. Someone proposed the concept of intelligent logistics. This concept has been continuously expanded and the requirements have become higher and higher. Finally, an intelligent logistics management supported by the Internet of Things technology has emerged. technology. In our school's research, we mainly proposed an intelligent distribution model based on the Internet of Things. This model not only optimizes the distribution process, but also proposes an efficient distribution strategy when faced with a large amount of data. This technology mainly uses the information interaction technology in the Internet of Things, which can ensure that the average delivery speed is the fastest, the average transportation distance is the shortest, and the time consumed in the logistics transmission process is the shortest. In the decision-making process of this intelligent distribution model, we must first establish some intelligent distribution models controlled by multiple indicators. During the experiment, we built a logistics perception system and used heuristic algorithms to solve the packing problem. Answered. The mainstream solution algorithm we use genetic algorithm, a large number of experiments and data show that this algorithm is scientifically based, and it has also exerted its due effect in application. This article mainly analyzes the impact of the intelligent logistics system provided by the Internet of Things technology, and then looks forward to the future development trend of the system. We hope that through the analysis of the status quo, we can promote the further development of my country's Internet of Things technology, and also promote the further development and optimization of my country's intelligent logistics system technology.

The NOAA-20 (N20) satellite was launched on November 18, 2017 carrying the second Visible Infrared Imaging Radiometer Suite (VIIRS) instrument. Immediately following the launch, the VIIRS passed a series of intensive calibration and validation tests, after which regular calibration and operation activities have continued successfully for more than three years. The production of NASA Collection 2 Level 1B (C2 L1B) for N20 VIIRS began in summer 2019. In this article, we evaluate the early mission performance of the N20 VIIRS reflective solar bands (RSB) covering the first three full years of operation. The calibrated RSB gains are calculated primarily from the onboard solar diffuser (SD) and used in generating the C2 L1B reflectance and radiance products. We also show the on-orbit performance of the instrument noise, signal-to-noise ratio (SNR), and a reflectance uncertainty assessment. Comparisons are made to the first three years of operation of the first VIIRS instrument, aboard the Suomi National Polar-orbiting Partnership (SNPP) satellite. We evaluate the long-term stability of the calibrated N20 RSB reflectance product by looking at the long-term trends of lunar observations and data from the pseudo-invariant Libya 4 desert site. The N20 RSB have had excellent early mission performance, with changes in the gain of less than 0.5% in the first three years across all detectors, stable L1B reflectance, and very stable values of detector SNR and reflectance uncertainty.

Clofarabine is approved for the treatment of relapsed or refractory acute lymphoblastic leukemia (ALL) in pediatric patients aged 1 to 21 years. Its pharmacokinetic (PK) exposure is strongly related to clinical outcomes and high risk of adverse reactions. PK-guided dosing of nucleoside analogs has the potential to improve survival and reduce toxicity in children. Considering that blood collection is an invasive operation and that the volume of blood collected is usually limited in pediatric ALL patients, a convenient and efficient method for the quantification of clofarabine in human urine and plasma was established with an LC-MS/MS system. Standard curves were shown to be liner in the range of 2.00-1000.00 ng mL

The earth-observing visible infrared imaging radiometer suite (VIIRS) on the Suomi National Polar-orbiting Partnership (SNPP) satellite regularly calibrates its reflective solar bands (RSBs), primarily through observing an onboard sunlit solar diffuser (SD). The on-orbit change of the value of the SD bidirectional reflectance distribution function (BRDF) is quantified by a numerical factor, called the H-factor, and is determined by the onboard SD stability monitor (SDSM). Because the spectral response function of an SDSM detector spreads in wavelength, the directly measured H-factor is the true H-factor convolved with the spectral response function. To find the true H-factor, we use the traditional direct method and an innovative iterative approach to separately deconvolve the measured H-factor. Our iterative approach relies on two properties of the SDSM detector spectral response function: the central peak width is narrow enough so that the H-factor does not change much over the peak width, and the dominance of the spectral response function's integral with respect to the wavelength over the width. The iterative approach is more accurate, of a smaller noise impact, much more flexible in terms of interpolation and extrapolation of functional values, and faster. We have used deconvolved H-factors to calibrate the NASA SNPP VIIRS RSB Collections 1 and 2 Level-1B products.

Integrating a proper amount of polymer hybrid of quaternary ammonium chloride functionalized graphitic carbon nitride (PHQACl-CN) in the perovskite leads to positive adjustments in the morphology of the treated perovskite films and boosts the PSC device performance.

Multidrug resistance (MDR) has been extensively reported in colorectal cancer patients, which remains a major cause of chemotherapy failure. One of the critical mechanisms of MDR in colorectal cancer is the reduced intracellular drug level led by the upregulated expression of the ATP‐binding cassette (ABC) transporters, particularly, ABCB1/P‐gp. In this study, the CRISPR/Cas9 system was utilized to target ABCB1 in MDR colorectal cancer SW620/Ad300 cell line with ABCB1 overexpression. The results showed that stable knockout of ABCB1 gene by the CRISPR/Cas9 system was achieved in the MDR cancer cells. Reversal of MDR against ABCB1 chemotherapeutic drugs increased intracellular accumulation of [3H]‐paclitaxel accumulation, and decreased drug efflux activity was observed in MDR SW620/Ad300 cells after ABCB1 gene knockout. Further tests using the 3D multicellular tumor spheroid model suggested that deficiency in ABCB1 restrained tumor spheroid growth and restore sensitivity to paclitaxel in MDR tumor spheroids. Overall, the CRISPR/Cas9 system targeting the ABCB1 gene can be an effective approach to overcome ABCB1‐mediated MDR in colorectal cancer SW620/Ad300 cells., In this study, the CRISPR/Cas9 system was utilized to target ABCB1 in multidrug resistant (MDR) colorectal cancer SW620/Ad300 cell line with ABCB1 overexpression. Knockout of ABCB1 gene resulted in reversal of MDR against ABCB1 chemotherapeutic drugs, increased intracellular accumulation of [3H]‐paclitaxel accumulation, and decreased drug efflux activity in MDR colon cancer cells. In a 3D multicellular tumor spheroid model, deficiency in ABCB1 restrained tumor spheroid growth and restore sensitivity to paclitaxel in MDR tumor spheroids.

Targeting P-glycoprotein (ABCB1 or P-gp) has been recognized as a promising strategy to overcome multidrug resistance. Here, we reported our medicinal chemistry efforts that led to the discovery of the triazolo[1,5-a]pyrimidine derivative WS-898 as a highly effective ABCB1 inhibitor capable of reversing paclitaxel (PTX) resistance in drug-resistant SW620/Ad300, KB-C2, and HEK293/ABCB1 cells (IC50 = 5.0, 3.67, and 3.68 nM, respectively), more potent than verapamil and zosuquidar. WS-898 inhibited the efflux function of ABCB1, thus leading to decreased efflux and increased intracellular PTX concentration in SW620/Ad300 cells. The cellular thermal shift assay indicated direct engagement of WS-898 to ABCB1. Furthermore, WS-898 stimulated the ATPase activity of ABCB1 but had minimal effects on cytochrome P450 3A4 (CYP3A4). Importantly, WS-898 increased PTX sensitization in vivo without obvious toxicity. The results suggest that WS-898 is a highly effective triazolo[1,5-a]pyrimidine-based ABCB1 inhibitor and shows promise in reversing ABCB1-mediated PTX resistance.

The Earth-observing Visible Infrared Imaging Radiometer Suite (VIIRS) on the Suomi National Polar-orbiting Partnership (SNPP) satellite regularly performs on-orbit radiometric calibration of its reflective solar bands (RSBs), primarily through observations of an onboard sunlit solar diffuser (SD). The on-orbit change of the SD bidirectional reflectance distribution function (BRDF) value, quantified by a numerical factor called the H-factor, is determined by the onboard SD stability monitor. Our previous study showed that the H-factor is solar angle- and view direction-dependent. In this study, we determine the dependence of the H-factor on the detector SD view footprint location. We fit an empirical model to the NASA Collection 1 SNPP VIIRS Level 1B (L1B) spectral reflectance difference across the detectors in an RSB over uniform Earth scenes of the Libya 4 desert and deep convective clouds (DCCs). We apply the model predicted SD-positional-dependent H-factor to calibrate the RSBs. Under this new calibration scheme, the original unreal striping is removed from the homogeneous Libya 4 desert and the DCC images, as well as the original unreal striping from the Dunhuang desert image. The SD-positional-dependent H-factor has been used to calculate the SNPP VIIRS RSB radiometric correction factor for the NASA Collection 2.0 SNPP VIIRS L1B products.

Perovskite solar cells(PSCs) are paid much attention due to simple preparation and high photoelectric conversion efficiency. Carbon nanofiber films(CNFs) prepared by electrospinning have high specific surface area, electrical properties and chemical stability, but the application in PSCs is limited due to their brittleness. The flexible and conductive Ag/ZrO2/C composite nanofiber films were prepared by electrospinning and hydrothermal method. After that, it was applied as the counter electrode of flexible PSCs and the effect of Ag nanoparticles with different concentrations on the performance of the composite nanofiber films and the PSCs were studied. The results show that when the concentration of precursor solution rises from 0 g/mL to 0.030 g/mL, the coating effect of Ag nanoparticles on the Ag/ZrO2/C composite nanofiber improves obviously and all the composite nanofiber films display the excellent flexibility and modulus of elasticity (0.479 MPa), meanwhile, the conductivity of the films increases from 866 S/m to 4862 S/m, so as to enhance the hole-electron transport capacity of the films and the performance of flexible PSCs. When the solution concentration is 0.030 g/mL, the PSCs have best photoelectric conversion efficiency(PCE) of 6.05% and optimal current density (18.44 mA/cm2). It is of great significance to further improve the performance of flexible PSCs and the application of flexible carbon nanofiber films.

Visible Infrared Imaging Radiometer Suite (VIIRS) radiometrically calibrates its reflective solar bands (RSBs) primarily through a sunlit onboard solar diffuser (SD). The sunlit SD provides a known radiance under the condition that the absolute product of the SD screen transmittance and the bidirectional reflectance distribution function (BRDF) along the SD-to-telescope direction is accurately known. The BRDF changes due to solar exposure. The change, referred to as the H-factor, is monitored by the onboard SD stability monitor (SDSM). The accuracy of the retrieved H-factor propagates to the retrieved F-factor which corrects the scene spectral radiance. High accuracy of the retrieved H-factor relies on high accuracies in the SDSM screen relative effective transmittance and the relative product of the SD screen effective transmittance and the BRDF at the mission start, and a high SDSM detector signal-to-noise ratio (SNR). This article briefly reviews the algorithms used for the NOAA-20 (N20) VIIRS RSB on-orbit radiometric calibration. Additionally, we show the performance of the N20 VIIRS SDSM, giving the SDSM detector SNRs and the SDSM detector gain temporal changes. We develop a model for the SNRs. The model shows that the decreased SNRs in time are due to the detector gain decreases. We also show the N20 VIIRS SD on-orbit performance, measured by the retrieved H-factor and the estimated standard deviation of its error. The H-factor for the telescope view is obtained from the H-factor for the SDSM view, multiplied by an H-factor angular dependence term. We use an innovative method to determine the angular dependence, using the dependence obtained for the Suomi National Polar-orbiting Partnership (SNPP) VIIRS.

Gastric cancer (GC) ranks fifth in global cancer diagnosis and fourth in cancer-related death. Despite tremendous progress in diagnosis and therapeutic strategies and significant improvements in patient survival, the low malignancy stage is relatively asymptomatic and many GC cases are diagnosed at advanced stages, which leads to unsatisfactory prognosis and high recurrence rates. With the recent advances in genome analysis, biomarkers have been identified that have clinical importance for GC diagnosis, treatment, and prognosis. Modern molecular classifications have uncovered the vital roles that signaling pathways, including EGFR/HER2, p53, PI3K, immune checkpoint pathways, and cell adhesion signaling molecules, play in GC tumorigenesis, progression, metastasis, and therapeutic responsiveness. These biomarkers and molecular classifications open the way for more precise diagnoses and treatments for GC patients. Nevertheless, the relative significance, temporal activation, interaction with GC risk factors, and crosstalk between these signaling pathways in GC are not well understood. Here, we review the regulatory roles of signaling pathways in GC potential biomarkers, and therapeutic targets with an emphasis on recent discoveries. Current therapies, including signaling-based and immunotherapies exploited in the past decade, and the development of treatment for GC, particularly the challenges in developing precision medications, are discussed. These advances provide a direction for the integration of clinical, molecular, and genomic profiles to improve GC diagnosis and treatments.

The ATP-binding cassette (ABC) transporter superfamily is one of the largest membrane protein families existing in wide spectrum of organisms from prokaryotes to human. ABC transporters are also known as efflux pumps because they mediate the cross-membrane transportation of various endo- and xenobiotic molecules energized by ATP hydrolysis. Therefore, ABC transporters have been considered closely to multidrug resistance (MDR) in cancer, where the efflux of structurally distinct chemotherapeutic drugs causes reduced itherapeutic efficacy. Besides, ABC transporters also play other critical biological roles in cancer such as signal transduction. During the past decades, extensive efforts have been made in understanding the structure-function relationship, transportation profile of ABC transporters, as well as the possibility to overcome MDR via targeting these transporters. In this review, we discuss the most recent knowledge regarding ABC transporters and cancer drug resistance in order to provide insights for the development of more effective therapies.

ATP‐binding cassette (ABC) transporters superfamily mediates multidrug resistance in cancer by extruding structurally distinct chemotherapeutic agents, causing failure in chemotherapy. Among the 49 ABC transporters, multidrug resistance protein 7 (MRP7 or ABCC10) is relatively new and has been identified as the efflux pump of multiple anticancer agents including Vinca alkaloids and taxanes. Herein, we construct and validate a homology model for human MRP7 based on the cryo‐EM structures of MRP1. Structure–function relationship of MRP7 was obtained from molecular dynamics simulations and docking studies and was in accordance with previous studies of ABC transporters. The motion patterns correlated with efflux mechanism were discussed. Additionally, predicted substrate‐ and modulator‐binding sites of MRP7 were described for the first time, which provided rational insights in understanding the drug binding and functional regulation in MRP7. Our findings will benefit the high‐throughput virtual screening and development of MRP7 modulators in the future., Homology modeling of MRP7 and predicted binding pocket characterization via docking analysis.

Hepatocellular carcinoma (HCC) is one of the most common cancers, and has an extremely poor prognosis. Our previous study confirmed that the microRNA miR-361-5p inhibited the proliferation, metastasis, invasiveness, and epithelial-to-mesenchymal transition (EMT) process of HCC by targeting the transcription factor Twist1. Long non-coding RNAs (lncRNAs) are key regulators of processes such as cell differentiation, inflammation, tumor formation, and immune escape. However, the underlying interactions between the lncRNA LINC00992, miR-361-5p, and Twist1 in HCC progression is still elusive. In the current study, the DIANA-lncBase database was used to identify regulatory genes upstream of miR-361-5p. Reverse transcription-quantitative PCR (RT-qPCR) was used to quantify the expression of the genes encoding LINC00992, miR-361-5p, and Twist1 in HCC cells. The cell counting kit-8 (CCK-8) was used to measure HCC cell proliferation and Transwell was used to measure HCC cell migration and invasion. The dual-luciferase reporter assay and RNA pull-down assay were performed to examine the interaction between LINC00992 and miR-361-5p. Western blotting was used to detect the levels of Twist1 protein. The result confirmed that, among three lncRNAs tested, miR-361-5p was the one most significantly affected by LINC00992. RT-qPCR revealed that LINC00992 was highly expressed in HCC tissues and cells. The follow-up results showed that the expression of LINC00992 and miR-361-5p in HCC tissues were closely correlated with the rate of metastasis or recurrence of the HCC patients. Our result showed that the expression of miR-361-5p was lower in the LINC00992 (+) group than in the LINC00992 (-) group. CCK-8 and Transwell showed that LINC00992 promoted HCC cell proliferation, migration, and invasion, whereas dual-luciferase reporter assay and RNA pull-down assay showed that LINC00992 combined with miR-361-5p to act as a miRNA decoy in HCC. RT-qPCR and Western blotting confirmed that LINC00992 upregulated the expression of the Twist1 gene in HCC cells by downregulating expression of miR-361-5p. CCK-8 and Transwell assays confirmed that LINC00992 promoted the proliferation, metastasis, and invasiveness of HCC cells by downregulating miR-361-5p levels and consequently upregulating Twist1 expression, implying that these three elements may be promising targets for HCC therapy.

Question answering is an indispensable link in high school teaching. Through question answering, on the one hand, it can solve students’ learning doubts, on the other hand, it can provide teachers with teaching feedback. However, through the investigation and research, it is found that with the expansion of student size, the effect of question answering in high school is not satisfactory. This paper analyzes the current situation of question answering in high school, and designs an intelligent question answering system for high school teaching based on constructivism learning theory and cognitive structure learning theory. The system, which is the first innovative application in the field of high school teaching, integrates knowledge graph technology and intelligent question answering technology, introduces big data technology. It can solve students’ questions in time and accurately, link the knowledge points related to the questions to help students construct knowledge network graph, and the big data technology is used to analyze the students’ questioning behavior and to predict students’ learning behavior in order to feedback the teaching effect.

The oxindole scaffold represents an important structural feature in many natural products and pharmaceutically relevant molecules. Herein, we report a visible-light-induced modular methodology for the synthesis of complex 3,3′-disubstituted oxindole derivatives. A library of valuable fluoroalkyl-containing highly sterically congested oxindole derivatives can be synthesized by a catalytic three-component radical coupling reaction under mild conditions (metal & photocatalyst free, >80 examples). This strategy shows high functional group tolerance and broad substrate compatibility (including a wide variety of terminal or non-terminal alkenes, conjugated dienes and enynes, and a broad array of polyfluoroalkyl iodide and oxindoles), which enables modular modification of complex drug-like compounds in one chemical step. The success of solar-driven transformation, large-scale synthesis, and the late-stage functionalization of bioactive molecules, as well as promising tumor-suppressing biological activities, highlights the potential for practical applications of this strategy. Mechanistic investigations, including a series of control experiments, UV-vis spectroscopy and DFT calculations, suggest that the reaction underwent a sequential two-step radical-coupling process and the photosensitive perfluoroalkyl benzyl iodides are key intermediates in the transformation.

Inspired by the nanostructure of bone, biomimetic nanocomposites comprising natural polymers and inorganic nanoparticles have gained much attention for bone regenerative applications. However, the mechanical and biological performances of nanocomposites are largely limited by the inhomogeneous distribution, uncontrolled size and irregular morphology of inorganic nanoparticles at present. In this work, an innovative in situ precipitation method has been developed to construct a biomimetic nanocomposite which consists of spherical hydroxyapatite (HA) nanoparticles and gelatin (Gel). The homogeneous dispersion of HA nanoparticles in nHA–Gel endowed it with a low swelling ratio, enhanced mechanical properties and slow degradation. Moreover, strontium (Sr) was incorporated into HA nanoparticles to further enhance the bioactivity of nanocomposites. In vitro experiments suggested that nHA–Gel and Sr–nHA–Gel facilitated cell spreading and promoted osteogenic differentiation of bone-marrow-derived mesenchymal stem cells (BMSCs) as compared to pure Gel and mHA–Gel conventional composites developed by mechanical mixing. In vivo rat critical-sized calvarial defect repair further confirmed that nHA–Gel and Sr–nHA–Gel possessed relatively effective bone regenerative abilities among the four groups. Collectively, the biomimetic nanocomposites of nHA–Gel and Sr–nHA–Gel have good efficacy in inducing bone regeneration and would be a promising alternative to bone grafts for clinical applications.

ABCB1 is a promising therapeutic target for overcoming multidrug resistance (MDR). In this work, we reported the structure-based design of triazolo[1,5-a]pyrimidines as new ABCB1 modulators, of which WS-691 significantly increased sensitization of ABCB1-overexpressed SW620/Ad300 cells to paclitaxel (PTX) (IC50 = 22.02 nM). Mechanistic studies indicated that WS-691 significantly increased the intracellular concentration of PTX and [3H]-PTX while decreasing the efflux of [3H]-PTX in SW620/Ad300 cells by inhibiting the efflux function of ABCB1. The cellular thermal shift assay suggested that WS-691 could stabilize ABCB1 by directly binding to ABCB1. WS-691 could stimulate the activity of ABCB1 ATPase but had almost no inhibitory activity against CYP3A4. Importantly, WS-691 increased the sensitivity of SW620/Ad300 cells to PTX in vivo without observed toxicity. Collectively, WS-691 is a highly potent and orally active ABCB1 modulator capable of overcoming MDR. The triazolo[1,5-a]pyrimidine may be a promising scaffold for developing more potent ABCB1 modulators.

Background Overexpression of ATP‐binding cassette (ABC) transporter is a major contributor to multidrug resistance (MDR), in which cancer cells acquire resistance to a wide spectrum of chemotherapeutic drugs. In this work, we evaluated the sensitizing effect of sitravatinib, a broad‐spectrum tyrosine kinase inhibitor (TKI), on ATP‐binding cassette subfamily B member 1 (ABCB1)‐ and ATP‐binding cassette subfamily C member 10 (ABCC10)‐mediated MDR. Methods MTT assay was conducted to examine cytotoxicity and evaluate the sensitizing effect of sitravatinib at non‐toxic concentrations. Tritium‐labeled paclitaxel transportation, Western blotting, immunofluorescence analysis, and ATPase assay were carried out to elucidate the mechanism of sitravatinib‐induced chemosensitization. The in vitro findings were translated into preclinical evaluation with the establishment of xenograft models. Results Sitravatinib considerably reversed MDR mediated by ABCB1 and partially antagonized ABCC10‐mediated MDR. Our in silico docking simulation analysis indicated that sitravatinib strongly and stably bound to the transmembrane domain of ABCB1 human‐mouse chimeric model. Furthermore, sitravatinib inhibited hydrolysis of ATP and synchronously decreased the efflux function of ABCB1. Thus, sitravatinib could considerably enhance the intracellular concentration of anticancer drugs. Interestingly, no significant alterations of both expression level and localization of ABCB1 were observed. More importantly, sitravatinib could remarkably restore the antitumor activity of vincristine in ABCB1‐mediated xenograft model without observable toxic effect. Conclusions The findings in this study suggest that the combination of sitrvatinib and substrate antineoplastic drugs of ABCB1 could attenuate the MDR mediated by the overexpression of ABCB1.

Nitrogen limitation is an important factor for the improvement of crop water production potential in rain-fed areas of the Loess Plateau. The reasonable deep application of nitrogen fertilizer is a promising method to increase yield of rain-fed crop. Based on APSIM model, this study simulated spring wheat yield under different nitrogen application rates and depths, by using meteorological observation data from 1990 to 2020 in the semiarid areas of central Gansu Province, aiming to provide theoretical reference for optimizing wheat fertilization strategy. The results showed that the determination coefficient of simulated spring wheat yield, biomass and soil water content in 0-200 cm soil profile was greater than 0.80, the normalized root mean square error was less than 0.2, and the model validity index was greater than 0.5. These results indicated that the model had good fitting and adaptability in the test area. Across all the levels within the experimental design, increasing nitrogen application rates could significantly increase the yield of spring wheat in different precipitation years, and increasing nitrogen application depth could significantly increase spring wheat yield in wet and normal years, but had no effect in dry years. The rate and depth of nitrogen application had significant interaction effects on spring wheat yield in wet and normal years, but not in dry years. According to the binary quadratic regression fitting equation, when the potential maximum yield reached 2749 kg·hm氮是限制黄土高原旱农区作物水分生产潜力提升的重要因素,而氮肥适度深施是旱地作物提效增产的有效措施。本研究利用甘肃省陇中地区1990—2020年气象观测数据,基于APSIM模型模拟了不同施氮量和施氮深度的春小麦产量,以期为优化陇中旱农区小麦施肥策略提供理论依据。结果表明: 模型模拟的春小麦产量、生物量和生育期0～200 cm土层土壤水分含量的相关性决定系数在0.8以上,归一化均方根误差均小于0.2,模型有效性检验高于0.5,表明APSIM模型在研究区域具有较好的适用性和模拟精度。在试验设计水平范围内,不同降水年型增加施氮量均能显著提高春小麦产量;增加施氮深度,可显著提高丰水年和平水年春小麦产量,对干旱年没有影响;施氮量和施氮深度对丰水年和平水年春小麦产量有显著交互效应,对干旱年没有影响。根据二元二次回归拟合方程可知,丰水年获得潜在最高产量(2749 kg·hm

Palbociclib was approved by the United States Food and Drug Administration for use, in combination with letrozole, as a first-line treatment for estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) postmenopausal metastatic breast cancer. However, recent studies show that palbociclib may be an inhibitor of the ABCB1 transporter, although this remains to be elucidated. Therefore, we conducted experiments to determine the interaction of palbociclib with the ABCB1 transporter. Our in vitro results indicated that the efficacy of palbociclib was significantly decreased in the ABCB1-overexpressing cell lines. Furthermore, the resistance of ABCB1-overexpressing cells to palbociclib was reversed by 3 μM of the ABCB1 inhibitor, verapamil. Moreover, the incubation of ABCB1-overexpressing KB-C2 and SW620/Ad300 cells with up to 5 μM of palbociclib for 72 h, significantly upregulated the protein expression of ABCB1. The incubation with 3 µM of palbociclib for 2h significantly increased the intracellular accumulation of [3H]-paclitaxel, a substrate of ABCB1, in ABCB1 overexpressing KB-C2 cells but not in the corresponding non-resistant parental KB-3-1 cell line. However, the incubation of KB-C2 cells with 3 μM of palbociclib for 72 h decreased the intracellular accumulation of [3H]-paclitaxel due to an increase in the expression of the ABCB1 protein. Palbociclib produced a concentration-dependent increase in the basal ATPase activity of the ABCB1 transporter (EC50 = 4.73 μM). Molecular docking data indicated that palbociclib had a high binding affinity for the ABCB1 transporter at the substrate binding site, suggesting that palbociclib may compete with other ABCB1 substrates for the substrate binding site of the ABCB1. Overall, our results indicate that palbociclib is a substrate for the ABCB1 transporter and that its in vitro anticancer efficacy is significantly decreased in cancer cells overexpressing the ABCB1.

Overcoming ATP-binding cassette subfamily G member 2 (ABCG2)-mediated multidrug resistance (MDR) has attracted the attention of scientists because one of the critical factors leading to MDR is the overexpression of ABCG2. Identification of novel chemotherapeutic reagents as inhibitors of ABCG2 has been considered an effective strategy. RN486, a Bruton’s Tyrosine Kinase (BTK) inhibitor, was discovered to potentially reverse ABCB1-mediated MDR. In this study, we reported that RN486 effectively antagonizes ABCG2-mediated MDR in cancer cells. Non-toxic concentrations of RN486 remarkably increased the sensitivity of ABCG2-overexpressing cancer cells to conventional anticancer drugs mitoxantrone and topotecan. The reversal mechanistic studies showed that RN486 increased the accumulation and decreased the efflux of ABCG2 substrate drug in ABCG2-overexpressing cancer cells. In addition, the inhibitory effect of RN486 on ABCG2-associated ATPase activity was also verified. Docking analysis indicated a strong binding between RN486 and ABCG2 transporter. Meanwhile, the AGCG2 subcellular localization and expression level were not altered by the treatment of RN486. Taken together, our studies suggest that RN486 can antagonize ABCG2-mediated MDR in cancer cells via interacting with ABCG2 and inhibiting the transporting function. RN486 could be potentially used in combination with chemotherapy against ABCG2-mediated MDR in cancers. Citation Format: Xing-Duo Dong, Qisi Lu, Yi-Dong Li, Qiu-Xu Teng, Zi-Ning Lei, Zhe-Sheng Chen. RN486, a Bruton’s tyrosine kinase inhibitor, reverses multidrug resistance in ABCG2-overexpressing cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2843.

Multidrug resistance (MDR) is the main cause of clinical treatment failure and poor prognosis in cancer. Targeting P-glycoprotein (P-gp) has been regarded as an effective strategy to overcome MDR. In this work, we reported our preclinical studies of the triazolo[1,5

With the advent of the digital twin era, the construction of digital twin engine based on basic twin data plays a very important role in future application scenarios such as intelligent monitoring, dynamic perception, scientific evaluation, intelligent prediction and intelligent decision-making. This paper mainly analyzes the definition of digital twin, the definition of digital twin model, data characteristics and the application scenario of digital twin, and puts forward a design framework and implementation method of digital twin data engine.

Highlights ABCB1 overexpression significantly desensitized both drug-selected and gene-transfected cells, which overexpress ABCB1, to OTS964 and that this drug resistance can be antagonized by verapamil, a known ABCB1 inhibitor. Consistently, a similar trend was observed in tumor-bearing mice. OTS964 stimulated ATPase activity of ABCB1 and upregulated expression levels of ABCB1, resulting in induced resistance to other ABCB1 substrate-drugs, such as paclitaxel. OTS964 received a comparable affinity score and can dock into the substrate-binding site of human ABCB1 protein.

Targeting P-glycoprotein (ABCB1 or P-gp) has been recognized as a promising strategy to overcome multidrug resistance. Here, we reported our medicinal chemistry efforts that led to the discovery of the triazolo[1,5

Type 2 diabetes (T2D) is a chronic metabolic disease characterized by hyperglycemia due to insulin resistance. Mounting evidence has correlated T2D to alterations in the composition of gut microbiota. Accordingly, targeting the gut microbiota has become an emerging strategy for T2D management. The aim of this article is to get a better insight into the rationale for targeting gut microbiota in T2D treatment. Thus, we herein reviewed the change of gut microbiota composition in T2D, factors shaping gut microbiota, and potential mechanisms behind the contribution of gut microbiota to T2D pathogenesis. At present, it has become possible to use intestinal microorganism capsules, bacteria liquid, and other preparations to carry out fecal microbiota transplantation for the treatment and intervention of T2D with insulin resistance and immune-mediated Type 1 diabetes (T1D).

The oxindole scaffold represents an important structural feature in many natural products and pharmaceutically relevant molecules. Herein, we report a visible-light-induced modular methodology for the synthesis of complex 3,3′-disubstituted oxindole derivatives. A library of valuable fluoroalkyl-containing highly sterically congested oxindole derivatives can be synthesized by a catalytic three-component radical coupling reaction under mild conditions (metal & photocatalyst free, >80 examples). This strategy shows high functional group tolerance and broad substrate compatibility (including a wide variety of terminal or non-terminal alkenes, conjugated dienes and enynes, and a broad array of polyfluoroalkyl iodide and oxindoles), which enables modular modification of complex drug-like compounds in one chemical step. The success of solar-driven transformation, large-scale synthesis, and the late-stage functionalization of bioactive molecules, as well as promising tumor-suppressing biological activities, highlights the potential for practical applications of this strategy. Mechanistic investigations, including a series of control experiments, UV-vis spectroscopy and DFT calculations, suggest that the reaction underwent a sequential two-step radical-coupling process and the photosensitive perfluoroalkyl benzyl iodides are key intermediates in the transformation., Simple, modular assembly of complex fluoroalkyl-containing oxindole derivatives with a broad scope and excellent functional group tolerance under mild conditions (metal- and photocatalyst-free). Benzyl iodides were identified as key intermediates.

Reported herein is an effective strategy for oxidative cross-coupling of indoles with various aldehydes. The strategy is based on a two-step transformation via a well-known Mannich-type reaction and a C-N bond cleavage for carbonyl introduction. The key step-the C-N bond cleavage of the Mannich product-was enabled by electrochemistry. This strategy (with over 40 examples) ensures excellent functional-group tolerance as well as late-stage functionalization of pharmaceutical molecules.

Overexpression of ABCB1 transporters plays a crucial role in mediating multidrug resistance (MDR). Therefore, it is important to inhibit ABCB1 activity in order to maintain an effective intracellular level of chemotherapeutic drugs. Tepotinib is a MET tyrosine kinase inhibitor with potential anticancer effect and it is currently in clinical trials. In this study, we investigated whether tepotinib could antagonize ABC transporters-mediated MDR. Our results suggest that tepotinib significantly reversed ABCB1-mediated MDR but not ABCG2- or ABCC1-mediated MDR. Mechanistic studies show that tepotinib significantly reversed ABCB1-mediated MDR by attenuating the efflux activity of ABCB1 transporter. The ATPase assay showed that tepotinib inhibited the ATPase activity of ABCB1 in a concentration-dependent manner. Furthermore, treatment with tepotinib did not change protein expression or subcellular localization of ABCB1. Docking analysis indicated that tepotinib interacted with the drug-binding site of the ABCB1 transporter. Our study provides a potential chemotherapeutic strategy of co-administrating tepotinib with other conventional chemotherapeutic agents to overcome MDR and improve therapeutic effect.

Cassava (Manihot esculenta), an important food crop in tropical areas, is well-adapted to drought conditions, but is sensitive to cold. The expression of MeTCP4, a transcription factor involved in the regulation of plant development and abiotic stresses responses, was altered under cold stress. However, its biological function under abiotic stress responses is still unclear. Here, we show that increased MeTCP4 expression enhances cold stress tolerance in Arabidopsis (Arabidopsis thaliana). To better understand the biological role of MeTCP4, the mRNA from overexpression and wild-type (WT) plants was isolated for whole genome sequencing to identify MeTCP4-mediated cold-responsive genes. Our results identify 1341 and 797 differentially expressed genes (DEGs) affected by MeTCP4 overexpression under normal and cold conditions, respectively. Gene ontology analysis revealed that a portion of the DEGs were involved in reactive oxygen species (ROS) metabolism process after cold treatment. qRT-PCR analysis revealed that the expression of cold-responsive genes and ROS-scavenging-related genes were increased in MeTCP4 overexpression plant, which could be responsible for the reduced ROS levels and enhanced cold resistance observed in transgenic plant. The findings provide insight into mechanisms of MeTCP4-mediated cold stress response, and provide clues for development of low temperature-tolerant cassava cultivars.

Background and aim: Alpha-momorcharin (α-MMC) is a type I ribosome-inactivating protein (RIP) that is purified from Momordica charantia. Despite its strong antitumor activities, α-MMC exerts the un...

ObjectivesDysregulated chondrocyte metabolism is closely associated with the pathogenesis of osteoarthritis (OA). Suppressing chondrocyte catabolism to restore cartilage homeostasis has been extensively explored, whereas far less effort has been invested toward enhancing chondrocyte anabolism. This study aimed to repurpose clinically approved drugs as potential stimulators of chondrocyte anabolism in treating OA.MethodsScreening of a Food and Drug Administration-approved drug library; Assays for examining the chondroprotective effects of digoxin in vitro; Assays for defining the therapeutic effects of digoxin using a surgically-induced OA model; A propensity-score matched cohort study using The Health Improvement Network to examine the relationship between digoxin use and the risk of joint OA-associated replacement among patients with atrial fibrillation; identification and characterisation of the binding of digoxin to low-density lipoprotein receptor-related protein 4 (LRP4); various assays, including use of CRISPR-Cas9 genome editing to delete LRP4 in human chondrocytes, for examining the dependence on LRP4 of digoxin regulation of chondrocytes.ResultsSerial screenings led to the identification of ouabain and digoxin as stimulators of chondrocyte differentiation and anabolism. Ouabain and digoxin protected against OA and relieved OA-associated pain. The cohort study of 56 794 patients revealed that digoxin use was associated with reduced risk of OA-associated joint replacement. LRP4 was isolated as a novel target of digoxin, and deletion of LRP4 abolished digoxin’s regulations of chondrocytes.ConclusionsThese findings not only provide new insights into the understanding of digoxin’s chondroprotective action and underlying mechanisms, but also present new evidence for repurposing digoxin for OA.

In this article, we present the novel approaches of characterizing and modeling the dynamic hystereses for magnetostrictive actuator. The output vs. input loops of the actuator exhibit dynamic hystereses with the different frequencies and amplitudes of sinusoidal currents. Experimental characterization of the dynamic hysteresis of the magnetostrictive actuator is conducted. Three indexes are quantitatively defined, i.e., loop relative width, loop asymmetry degree, and output nonlinearity degree. The polynomial-modified Prandtl-Ishlinskii (PMPI) and adaptive infinite impulse response (IIR) integrated modeling approach is proposed to perform the dynamic hysteresis identification. Therein, the PMPI model is utilized to describe the hysteresis, while the dynamics is modeled via the IIR model. The parameters of PMPI and IIR model are acquired by the data-fitting and recursive least squares (RLS) algorithm respectively. Experimental characterization results show that the magnetostrictive dynamic hysteresis possesses strong nonlinear and asymmetry. Comparison of theoretical modeling and measurement results demonstrates that the PMPI and adaptive IIR integrated model is effective to describe dynamic hysteresis of the magneostrictive actuator.

Multidrug resistance-associated protein 7 (MRP7) is an important member of ABC transporter superfamily and has been revealed to mediate the cross-membrane translocation of a wide range of chemotherapeutic agents including taxanes, epothilones, Vinca alkaloids, Anthracyclines and Epipodophyllotoxins.In our previous study, a 1,2,3-triazole-pyrimidine hybridCMP25was synthesized and found able to efficiently reverse multidrug resistance (MDR) mediated by P-glycoprotein. In this study, we evaluated the efficacy of compound CMP25in reversing MDR mediated by MRP7in vitro. The results showed that CMP25significantly sensitized MRP7-overexpressing cells to anticancer drugs that are MRP7 substrates. Mechanistic study showed that CMP25reversed MRP7-mediated MDR by increasing the intracellular accumulation of anticancer drugs and decreasing drug efflux, without altering protein expression level or subcellular localization. Currently, very few studies on synthetic MRP7 modulators have been published. Our findings provide a valuable prototype for designing drugs to combine with conventional anticancer drugs to overcome MDR-mediated by MRP7.

Both reasonable soil tillage and fertilization management play critical roles in improving the yield and water use efficiency (WUE) of forage maize in the semi-arid area of Loess Plateau. A field experiment was conducted at Dingxi experimental station of Gansu Academy of Agricultural Sciences between 2017 and 2019. We explored the effects of tillage method and fertilization type on yields and WUE of forage maize, as well as the economic benefits. There were four treatments in the experiment, including traditional rotary tillage + organic-inorganic fertilization (TOF), deep rotary tillage + organic-inorganic fertilization (DOF), and vertical rotary subsoiling + organic-inorganic fertilization (VROF), and the traditional rotary tillage + inorganic fertilization as the control (TF). Our results showed that, compared with DOF, TOF, TF, and VROF all decreased soil water storage in 0-300 cm soil layer at flowering stage, ranging from 16.9 mm to 79.9 mm, but they all increased soil water consumption by 9.7-22.4 mm during vegetative growing stages, 11.0-19.8 mm during reproductive stage in the dry years. Due to significant improvement in water absorption, VROF increased dry matter weight at maturity by 3.9%-13.4% compared to other treatments. Similarly, plant height, ear length, grain number per ear, 100-grain weight, and double ear rate under VROF were significantly increased, while bald head length was decreased significantly, when compared with other treatments. As a result, over the three experimental seasons, VROF increased the grain and biological yield by 4.3%-51.5% and 4.3%-25.7% compared to other treatments, respectively. Accordingly, WUE calculated by grain and biomass yields were increased by 2.7%-36.9% and 3.6%-13.5% under VROF, compared to other treatments. VROF increased the unit gross total output value and the net income by 5.1%-32.9% and 6.9%-80.5% respectively, compared to other treatments. These results demonstrated that VROF is a drought-resistant and yield-increasing farming technology for sustainable forage maize production in the semi-arid area of the Loess Plateau, Northwest China.合理的耕作和施肥管理措施是提高黄土高原半干旱区饲用玉米产量和水分利用效率的关键。本研究于2017—2019年在甘肃省农业科学院定西试验站开展大田试验,设置了传统旋耕+有机无机肥配施(TOF)、深旋耕+有机无机肥配施(DOF)和立式深旋耕+有机无机肥配施(VROF)3个处理,并以传统旋耕+单施无机肥(TF)为对照,测定了饲用玉米干物质量、土壤含水量、产量,计算了土壤耗水量、水分利用效率和经济效益等指标,探究不同处理对饲用玉米产量、水分利用效率和经济效益的影响。结果表明: 与其他处理相比,VROF花期0～300 cm土层土壤贮水量降低了16.9～79.9 mm,干旱年份花前耗水量增加了9.7～22.4 mm、花后耗水量增加了11.0～19.8 mm,总土壤耗水量提高了8.6%～12.4%;立式深旋耕+有机无机肥配施能够促进饲用玉米生育期耗水,使得成熟期干物质量增加3.9%～13.4%,株高、穗长、穗粒数、百粒重和双穗率也明显增加,秃顶长显著降低,籽粒产量增加4.3%～51.5%、生物产量增加4.3%～25.7%,籽粒和生物量水分利用效率分别提高2.7%～36.9%和3.6%～13.5%,单位总产值增加5.1%～32.9%、纯收益提高6.9%～80.5%。可知,立式深旋耕结合有机无机肥配施能够调控饲用玉米生育期耗水,使饲用玉米干物质积累、株高、百粒重等农艺和经济性状指标明显增加,显著提升产量和水分利用效率,并提高总产值和纯收益,是适宜于西北黄土高原半干旱区饲用玉米种植的抗旱增产增效技术。.

Overexpression of ATP-binding cassette transporter superfamily G member 2 (ABCG2), is known as a major mechanism mediating multidrug resistance (MDR) in cancer cells. MLN7243 is a small-molecule ubiquitin activating enzyme inhibitor currently under clinical investigation. The aim of the current study is to determine if MLN7243 is a substrate of MDR-related ABCG2 transporter. Our results showed that cancer cells overexpressing ABCG2 transporter were resistant to MLN7243 compared to the parental cells, while knockout of ABCG2 gene or pharmacological inhibition of ABCG2 efflux function completely reversed the drug resistance. Unexpectedly, the endogenous low expression of ABCG2 is sufficient to confer cancer cells resistance to MLN7243. The ABCG2 ATPase assay and HPLC assay suggested that MLN7243 can significantly stimulate ABCG2 ATPase activity and be pumped out from ABCG2-overexpressing cells by ABCG2. The docking analysis also implied that MLN7243 binds to ABCG2 drug-binding pocket with optimal binding affinity. However, MLN7243 did not competitively inhibit the efflux of other ABCG2 substrate drugs, indicating it may not serve as an MDR reversal agent. In conclusion, our study provides direct in vitro evidence to show that MLN7243 is a potent ABCG2 substrate. If our results can be translated to humans, it suggests that combining MLN7243 with ABCG2 inhibitors may enhance the anticancer efficacy for patients with high tumor ABCG2 level.

Cabozantinib (CBZ) is a small molecule tyrosine kinase receptor inhibitor, which could also inhibit the ABCG2 transporter function. Therefore, CBZ could re-sensitize cancer cells that are resistant to ABCG2 substrate drugs including topotecan (TPT). However, its reversal effect against TPT resistance has not been tested in a TPT-induced resistant cancer model. In this study, a new TPT selected human non-small cell lung cancer (NSCLC)-resistant cell model NCI-H460/TPT10 with ABCG2 overexpression and its parental NCI-H460 cells were utilized to investigate the role of CBZ in drug resistance. The in vitro study showed that CBZ, at a non-toxic concentration, could re-sensitize NCI-H460/TPT10 cells to TPT by restoring intracellular TPT accumulation via inhibiting ABCG2 function. In addition, the increased cytotoxicity by co-administration of CBZ and TPT may be contributed by the synergistic effect on downregulating ABCG2 expression in NCI-H460/TPT10 cells. To further verify the applicability of the NCI-H460/TPT10 cell line to test multidrug resistance (MDR) reversal agents in vivo and to evaluate the in vivo efficacy of CBZ on reversing TPT resistance, a tumor xenograft mouse model was established by implanting NCI-H460 and NCI-H460/TPT10 into nude mice. The NCI-H460/TPT10 xenograft tumors treated with the combination of TPT and CBZ dramatically reduced in size compared to tumors treated with TPT or CBZ alone. The TPT-resistant phenotype of NCI-H460/TPT10 cell line and the reversal capability of CBZ in NCI-H460/TPT10 cells could be extended from in vitro cell model to in vivo xenograft model. Collectively, CBZ is considered to be a potential approach in overcoming ABCG2-mediated MDR in NSCLC. The established NCI-H460/TPT10 xenograft model could be a sound clinically relevant resource for future drug screening to eradicate ABCG2-mediated MDR in NSCLC.