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Abstract The prediction of the efficiency of oil well pumping systems plays an important role in optimizing the energy efficiency parameters of these systems. Currently, the prediction of oil well pumping system efficiency relies primarily on mechanistic models, but these models are often overly complex in predicting efficiency. Some researchers have attempted to use deep learning to predict system efficiency, but due to insufficient consideration of influencing factors and the causal relationships between these factors and system efficiency, they often include irrelevant variables as influencing factors, leading to less accurate prediction models. In this paper, a hybrid model (MDS–SSA–GNN) is proposed for the prediction of pumping well system efficiency. The model consists of six parts: Pearson's product moment correlation coefficient (PPMCC), multidimensional scaling (MDS) transform, maximum–minimum normalization, sparrow optimization algorithm (SSA), graph neural network (GNN), and maximum–minimum inverse normalization. First, the size of the correlation coefficient between each influencing factor and the system efficiency is quantitatively calculated by using PPMCC. Second, the main influencing factors are downscaled by using MDS and normalized based on the principle of maximum–minimum normalization. Third, the GNN algorithm is used for the prediction of the pumping unit system efficiency, and the SSA algorithm is used for the optimization of the initial values of the network parameters. Finally, the prediction results are obtained by the maximum–minimum antinormalization. To validate the model's accuracy, this study randomly selected 100 actual oil wells for comparative analysis and analyzed the impact of structural parameters of the hybrid algorithm on the prediction accuracy of system efficiency. The analysis results demonstrate that the proposed model can effectively predict system efficiency and has a certain role in improving the accuracy of oil well pumping system efficiency predictions.

Abstract Ethylene regulates plant growth, development, and stress adaptation. However, the early signaling events following ethylene perception, particularly in the regulation of ethylene receptor/CTRs (CONSTITUTIVE TRIPLE RESPONSE) complex, remains less understood. Here, utilizing the rapid phospho-shift of rice OsCTR2 in response to ethylene as a sensitive readout for signal activation, we revealed that MHZ3, previously identified as a stabilizer of ETHYLENE INSENSITIVE 2 (OsEIN2), is crucial for maintaining OsCTR2 phosphorylation. Genetically, both functional MHZ3 and ethylene receptors prove essential for OsCTR2 phosphorylation. MHZ3 physically interacts with both subfamily I and II ethylene receptors, e.g., OsERS2 and OsETR2 respectively, stabilizing their association with OsCTR2 and thereby maintaining OsCTR2 activity. Ethylene treatment disrupts the interactions within the protein complex MHZ3/receptors/OsCTR2, reducing OsCTR2 phosphorylation and initiating downstream signaling. Our study unveils the dual role of MHZ3 in fine-tuning ethylene signaling activation, providing insights into the initial stages of the ethylene signaling cascade.

Abstract The CLIP1-LTK fusion was recently discovered as a novel oncogenic driver in non-small cell lung cancer (NSCLC). Lorlatinib, a third-generation ALK inhibitor, exhibited a dramatic clinical response in a NSCLC patient harboring CLIP1-LTK fusion. However, it is expected that acquired resistance will inevitably develop, particularly by LTK mutations, as observed in NSCLC induced by oncogenic tyrosine kinases treated with corresponding tyrosine kinase inhibitors (TKIs). In this study, we evaluate eight LTK mutations corresponding to ALK mutations that lead to on-target resistance to lorlatinib. All LTK mutations show resistance to lorlatinib with the L650F mutation being the highest. In vitro and in vivo analyses demonstrate that gilteritinib can overcome the L650F-mediated resistance to lorlatinib. In silico analysis suggests that introduction of the L650F mutation may attenuate lorlatinib-LTK binding. Our study provides preclinical evaluations of potential on-target resistance mutations to lorlatinib, and a novel strategy to overcome the resistance.

Objective To analyze the current status of drug compliance and influencing factors of oral anti-tumor targeted drugs in elderly patients with colon cancer after discharge. Methods A total of 110 elderly patients with colon cancer admitted to the First Affiliated Hospital of Harbin Medical University from February 2022 to February 2023 were selected.All patients received oral anti-tumor targeted drug therapy after discharge.Morisky medication compliance questionnaire was used to assess medication compliance, and then the factors affecting medication compliance were statistically analyzed. Results A total of 34 patients had good compliance(good compliance group) and 76 patients had poor compliance (poor compliance group).Univariate analysis showed that the proportion of lack of social support, adverse reactions to oral targeted drug therapy, adverse psychological reactions, poor economic conditions, and lack of knowledge of oral targeted drug therapy in the poor compliance group was significantly higher than that in the good compliance group, and the differences were statistically significant(P

Abstract Peripheral T cell lymphomas are typically aggressive with a poor prognosis. Unlike other hematologic malignancies, the lack of target antigens to discriminate healthy from malignant cells limits the efficacy of immunotherapeutic approaches. The T cell receptor expresses one of two highly homologous chains [T cell receptor β-chain constant (TRBC) domains 1 and 2] in a mutually exclusive manner, making it a promising target. Here we demonstrate specificity redirection by rational design using structure-guided computational biology to generate a TRBC2-specific antibody (KFN), complementing the antibody previously described by our laboratory with unique TRBC1 specificity (Jovi-1) in targeting broader spectrum of T cell malignancies clonally expressing either of the two chains. This permits generation of paired reagents (chimeric antigen receptor-T cells) specific for TRBC1 and TRBC2, with preclinical evidence to support their efficacy in T cell malignancies.

Abstract Plants can autonomously adjust their growth direction based on the gravitropic response to maximize energy acquisition, despite lacking nerves and muscles. Endowing soft robots with gravitropism may facilitate the development of self‐regulating systems free of electronics, but remains elusive. Herein, acceleration‐regulated soft actuators are described that can respond to the gravitational field by leveraging the unique fluidity of liquid metal in its self‐limiting oxide skin. The soft actuator is obtained by magnetic printing of the fluidic liquid metal heater circuit on a thermoresponsive liquid crystal elastomer. The Joule heat of the liquid metal circuit with gravity‐regulated resistance can be programmed by changing the actuator's pose to induce the flow of liquid metal. The actuator can autonomously adjust its bending degree by the dynamic interaction between its thermomechanical response and gravity. A gravity‐interactive soft gripper is also created with controllable grasping and releasing by rotating the actuator. Moreover, it is demonstrated that self‐regulated oscillation motion can be achieved by interfacing the actuator with a monostable tape spring, allowing the electronics‐free control of a bionic walker. This work paves the avenue for the development of liquid metal‐based reconfigurable electronics and electronics‐free soft robots that can perceive gravity or acceleration.

Hydraulic fracturing technology is an effective way to develop tight sandstone reservoirs with low porosity and permeability. The tight sandstone reservoir is heterogeneous and the heterogeneity characteristics has an important influence on fracture propagation. To investigate hydraulic fracture performance in heterogeneous tight reservoir, the X-ray diffraction experiments are carried out, the Weibull distribution method and finite element method are applied to establish the uniaxial compression model and the hydraulic fracture propagation model of heterogeneous tight sandstone. Meanwhile, the sensitivity of different heterogeneity characterization factors and the multi-fracture propagation mechanism during hydraulic fracture propagation is analyzed. The results indicate that the pressure transfer in the heterogeneous reservoir is non-uniform, showing a multi-point initiation fracture mode. For different heterogeneity characterization factors, the heterogeneity characteristics based on elastic modulus are the most sensitive. The multi-fracture propagation of heterogeneous tight sandstone reservoir is different from that of homogeneous reservoir, the fracture propagation morphology is more complex. With the increase of stress difference, the fracture propagation length increases. With the increase of injection rate, the fracture propagation length increases. With the increase of cluster spacing, the propagation length of multiple fractures tends to propagate evenly. This study clarifies the influence of heterogeneity on fracture propagation and provides some guidance for fracturing optimization of tight sandstone reservoirs.

Herein, we report a (PPh3)2Ni(o-tolyl)Cl complex-catalyzed cyclotrimerisation reaction of diynes and alkynes to furnish multi-substituted benzene derivatives in moderate to excellent yields. This method features an air-stable catalyst, green reaction conditions, and excellent functional group tolerance. Additionally, this approach enables gram-scale synthesis, and the target product could also be further derivatised into important isoindolinone scaffolds. These demonstrate the potential application of this methodology.

Abstract Ethylene plays essential roles in rice growth, development and stress adaptation. Translational control of ethylene signaling remains unclear in rice. Here, through analysis of an ethylene-response mutant mhz9, we identified a glycine-tyrosine-phenylalanine (GYF) domain protein MHZ9, which positively regulates ethylene signaling at translational level in rice. MHZ9 is localized in RNA processing bodies. The C-terminal domain of MHZ9 interacts with OsEIN2, a central regulator of rice ethylene signaling, and the N-terminal domain directly binds to the OsEBF1/2 mRNAs for translational inhibition, allowing accumulation of transcription factor OsEIL1 to activate the downstream signaling. RNA-IP seq and CLIP-seq analyses reveal that MHZ9 associates with hundreds of RNAs. Ribo-seq analysis indicates that MHZ9 is required for the regulation of ~ 90% of genes translationally affected by ethylene. Our study identifies a translational regulator MHZ9, which mediates translational regulation of genes in response to ethylene, facilitating stress adaptation and trait improvement in rice.

Olaquindox (OLA) and quinocetone (QCT) have been prohibited in aquatic products due to their significant toxicity and side effects. In this study, rapid and visual europium nanoparticle (EuNP)-based lateral flow strip biosensors (LFSBs) were developed for the simultaneous quantitative detection of OLA, QCT, and 3-methyl-quinoxaline-2-carboxylic acid (MQCA) in fish feed and tissue. The EuNP-LFSBs enabled sensitive detection for OLA, QCT, and MQCA with a limit of detection of 0.067, 0.017, and 0.099 ng/mL (R2 ≥ 0.9776) within 10 min. The average recovery of the EuNP-LFSBs was 95.13%, and relative standard deviations were below 9.38%. The method was verified by high-performance liquid chromatography (HPLC), and the test results were consistent. Therefore, the proposed LFSBs serve as a powerful tool to monitor quinoxalines in fish feeds and their residues in fish tissues.

The spline teeth fracture of separator plates in wet multi-plate clutches compromises driving safety and the vehicle’s lifespan. Tooth fracture is mainly caused by stress concentration at the tooth root and uneven circumferential load distribution. This paper considers parameters such as torque, teeth count, tooth profile, and misalignment errors, establishing the corresponding finite element (FE) model to analyze the impact of the above-mentioned parameters on the strength of the separator plates. Analysis under even and biased load circumstances demonstrated that an optimum tooth count and profile can significantly increase the strength of the separator plates, offering advice for the optimized design of wet multi-plate clutch separator plates.

The H5N1 avian influenza virus seriously affects the health of poultry and humans. Once infected, the mortality rate is very high. Therefore, accurate and timely detection of the H5N1 avian influenza virus is beneficial for controlling its spread. This article establishes a dual gene detection method based on dual RPA for simultaneously detecting the HA and M2 genes of H5N1 avian influenza virus, for the detection of H5N1 avian influenza virus. Design specific primers for the conserved regions of the HA and M2 genes. The sensitivity of the dual RT-RPA detection method for HA and M2 genes is 1 × 10−7 ng/μL. The optimal primer ratio is 1:1, the optimal reaction temperature is 40 °C, and the optimal reaction time is 20 min. Dual RT-RPA was used to detect 72 samples, and compared with RT-qPCR detection, the Kappa value was 1 (p value < 0.05), and the clinical sample detection sensitivity and specificity were both 100%. The dual RT-RPA method is used for the first time to simultaneously detect two genes of the H5N1 avian influenza virus. As an accurate and convenient diagnostic tool, it can be used to diagnose the H5N1 avian influenza virus.

Small molecules are significant risk factors for causing food safety issues, posing serious threats to human health. Sensitive screening for hazards is beneficial for enhancing public security. However, traditional detection methods are unable to meet the requirements for the field screening of small molecules. Therefore, it is necessary to develop applicable methods with high levels of sensitivity and specificity to identify the small molecules. Aptamers are short−chain nucleic acids that can specifically bind to small molecules. By utilizing aptamers to enhance the performance of recognition technology, it is possible to achieve high selectivity and sensitivity levels when detecting small molecules. There have been several varieties of aptamer target recognition techniques developed to improve the ability to detect small molecules in recent years. This review focuses on the principles of detection platforms, classifies the conjugating methods between small molecules and aptamers, summarizes advancements in aptamer−based conjugate recognition techniques for the detection of small molecules in food, and seeks to provide emerging powerful tools in the field of point−of−care diagnostics.

The reduction of friction-induced noise is a crucial research area for enhancing vehicle comfort, and this paper proposes a method based on circular pit texture to achieve this goal. We conducted a long-term sliding friction test using a pin-on-disc friction and a wear test bench to verify the validity of this method. To compare the friction noise of different surfaces, texture units with varying line densities were machined on the surface of friction disk samples. The resulting friction-wear and noise characteristics of the samples were analyzed in conjunction with the microscopic morphology of the worn surfaces. The results indicate that surfaces with textures can delay the onset of squeal noise, and the pattern of its development differs from that of smooth surfaces. The noise reduction effect is most evident due to the proper distribution of textures that can form furrow-like wear marks at the wear interface. The finite element results demonstrate that this morphology can improve pressure distribution at the leading point and reduce the tendency of system instability.

Phase change materials (PCMs) can regulate the temperature in asphalt pavement and minimize temperature-related problems, such as rutting and thermal cracking, because of their ability to store and release latent heat. Suitable PCMs can also enable additional road surface functions, such as snow melting ability, freeze-thaw cycle resistance, and heat island reduction. These functions are helpful in achieving intelligent, green, and sustainable transportation systems. Although the research on PCMs for asphalt pavement has been carried out for more than 10 years, a systematic material system and mature application technology have not yet been formed. The main reasons for restricting the development of this technology include the lack of suitability between the PCMs and asphalt pavement, the quantitative characterization of phase change temperature regulation property, and the evaluation of the effect of phase change energy storage on improving pavement performance. Although the published review has made a comprehensive summary of the existing research, it has yet to identify the key restricting the development of this technology and carry out a review and discussion based on it. To grasp the development status of the application of PCMs in asphalt pavement, sort out the development needs and break through the technical barriers, this study systematically summarizes the preparation and performance of PCMs for asphalt pavement, compares the performance and evaluation methods of asphalt mixtures with different PCMs, and summarizes the numerical simulation methods of phase change asphalt mixtures. Finally, this study presents potential approaches to address critical technical issues and discusses possible future research.

Magnetic soft robots featuring untethered actuation and high mechanical compliance have promising applications ranging from bionics to biomedicine. However, their fixed magnetization profiles pose a challenge for adaptive shape transformation in unpredictable environments and dynamic tasks. Herein, a reprogrammable magnetic soft composite is reported by encapsulating magnetic neodymium–iron–boron microparticles with low melting alloy (LMA) and embedding them into the elastomer. Utilizing the phase transition of the LMA, the magnetic microparticles can be reoriented under an external magnetic field and they can be immobilized through LMA solidification, allowing the robot to obtain a new magnetization profile corresponding to its temporary shape. By changing the LMA composition, the robot with multiple programming temperatures can be fabricated and its local magnetization profiles can be selectively programmed in different temperature ranges. A bioinspired crawler with multimode locomotion, a reconfigurable robotic gripper capable of adaptable grasping, and reconfigurable electronic circuits are also demonstrated. This work may pave the way for the next‐generation magnetic soft robots and reconfigurable devices.

Cynomorium songaricum Rupr. (CSR) belongs to the family Cynomoriaceae. It is a perennial succulent parasitic herb with a reddish-brown coloration, predominantly submerged in sand and lacking chlorophyll. Traditionally, it has been used in ethnic medicine to treat various diseases, such as gastric ulcers, indigestion, bowel movements, and improving sexual function. To comprehensively collect CSR data, extensive literature searches were conducted using medical, ecological, and scientific databases such as Google Scholar, PubMed, Science Direct, Web of Science, and China National Knowledge Infrastructure (CNKI). This article summarizes and categorizes research on the uses, phytochemical characteristics, pharmacological activities, and toxicity of ethnic medicine, with the aim of establishing a solid foundation and proposing new avenues for exploring and developing potential applications of CSR. So far, a total of 98 compounds have been isolated and identified from CSR, including flavonoids, terpenes, steroids, and other compounds. It is worth noting that flavonoids and polysaccharides have significant antioxidant and anti-inflammatory properties. In addition, these compounds also show good application prospects in anti-tumor, antioxidant, anti-aging, anti-fatigue, anti-diabetes, and other aspects. Although extensive progress has been made in the basic research of CSR, further research is still needed to enhance the understanding of its mechanism of action and explore more unknown compounds. Our review indicates that CSR has broad prospects and deserves further research.

The landscape diversity index (LDI) is an important level in biodiversity conservation, and its scale dependence has an important role in regional landscape planning and biological conservation. The aim of this study is to analyze in depth the effects of spatial scale changes in the classification of different landscape components on LDI and to explore the thresholds of LDI. The classification of landscape components was accomplished in the ArcMap environment using fusion and merging tools, and the LDI thresholds and scale changes were quantitatively assessed by LDI values. The results show that there are differences in LDI values for different classifications, and the threshold for LDI without considering scale changes can be interpreted as: 0.4215 ≤ LDI ≤ 1.9754. The grain sizes suitable for landscape diversity analysis are 160m and 1280 m, and the effective amplitude range of the I, II and III land type is 9~31 km, while the effective amplitude of three land use types is 20∼31 km, relatively lagging behind. However, when considering amplitude changes, the LDI threshold can be interpreted as 0.3027 ≤ LDI ≤ 2.0947, which is suitable for large-scale regional landscape diversity studies when the grain size is large. In conclusion, the essence of landscape diversity change with scale is caused by changes in the number and area of landscape components, and the threshold analysis should not only take into account the grain size and amplitude, but also consider the landscape background of the study area.

ING1 is a chromatin targeting subunit of the Sin3a histone deacetylase (HDAC) complex that alters chromatin structure to subsequently regulate gene expression. We find that ING1 knockdown increases expression of Twist1, Zeb 1&2, Snai1, Bmi1 and TSHZ1 drivers of EMT, promoting EMT and cell motility. ING1 expression had the opposite effect, promoting epithelial cell morphology and inhibiting basal and TGF-β-induced motility in 3D organoid cultures. ING1 binds the Twist1 promoter and Twist1 was largely responsible for the ability of ING1 to reduce cell migration. Consistent with ING1 inhibiting Twist1 expression in vivo, an inverse relationship between ING1 and Twist1 levels was seen in breast cancer samples from The Cancer Genome Atlas (TCGA). The HDAC inhibitor vorinostat is approved for treatment of multiple myeloma and cutaneous T cell lymphoma and is in clinical trials for solid tumours as adjuvant therapy. One molecular target of vorinostat is INhibitor of Growth 2 (ING2), that together with ING1 serve as targeting subunits of the Sin3a HDAC complex. Treatment with sublethal (LD25-LD50) levels of vorinostat promoted breast cancer cell migration several-fold, which increased further upon ING1 knockout. These observations indicate that correct targeting of the Sin3a HDAC complex, and HDAC activity in general decreases luminal and basal breast cancer cell motility, suggesting that use of HDAC inhibitors as adjuvant therapies in breast cancers that are prone to metastasize may not be optimal and requires further investigation.

Avian influenza is caused by avian influenza virus infection; the H5N1 avian influenza virus is a highly pathogenic subtype, affecting poultry and human health. Since the discovery of the highly pathogenic subtype of the H5N1 avian influenza virus, it has caused enormous losses to the poultry farming industry. It was recently found that the H5N1 avian influenza virus tends to spread among mammals. Therefore, early rapid detection methods are highly significant for effectively preventing the spread of H5N1. This paper discusses the detection technologies used in the detection of the H5N1 avian influenza virus, including serological detection technology, immunological detection technology, molecular biology detection technology, genetic detection technology, and biosensors. Comparisons of these detection technologies were analyzed, aiming to provide some recommendations for the detection of the H5N1 avian influenza virus.

Graphene is considered a good lubricant additive. The lubricating properties of graphene lubricant at different concentrations and temperatures are studied via a four-ball friction and wear-testing machine. The results show that the coefficient of friction (COF) and wear scar diameter (WSD) of the steel ball with 0.035 wt% graphene lubricant decreased by 40.8% and 50.4%, respectively. Finally, through surface analysis, the following lubrication mechanism is proposed: as the added graphene particles can easily fill and cover the pores of the friction surface, the contact pressure of the rough peak is reduced, resulting in a lower COF and smoother surface. Although the COF increases with temperature, graphene lubricants still exhibit good lubrication effects.

To solve grid-scale problems and evaluation indicator selection in landscape ecological risk index (LERI) evaluation, this paper takes the Bailong River Basin in Gansu Province (BLRB) as an example. The LERI evaluation formulae and optimal grid scales were determined by screening landscape indices and area changes in the LERI at different grid scales. The evaluation indices were finally obtained according to the landscape characteristics and the correlation analysis of the landscape index value. Through the statistical analysis of the area of the LERI at the grid scale of 1–6 km, the optimal grid scale was determined to be 5 km. There was little change in land use patterns, with the most significant increases in artificial surfaces at 3.29% and 3.58%, respectively. Cultivated land was the only land use type to decrease by 184.3 km2. The LERI drops with the reduced cultivated land area; the landscape ecological medium risk area and cultivated land keep the same spatial distribution. Due to the limitation of the topography, cultivated land is generally distributed below 2500 m altitude, so 2500 m becomes the turning point in the spatial distribution of the LERI. The medium risk below 2500 m dominates the LERI type. Reduced cultivated land was the leading cause of reduced ecological risk according to an overlay analysis. The study of LERI evaluations provides a theoretical basis for sustainable and ecological environmental protection in the BLRB.

The recent pandemic of SARS-CoV-2 has underscored the critical need for rapid and precise viral detection technologies. Point-of-care (POC) technologies, which offer immediate and accurate testing at or near the site of patient care, have become a cornerstone of modern medicine. Prokaryotic Argonaute proteins (pAgo), proficient in recognizing target RNA or DNA with complementary sequences, have emerged as potential game-changers. pAgo present several advantages over the currently popular CRISPR/Cas systems-based POC diagnostics, including the absence of a PAM sequence requirement, the use of shorter nucleic acid molecules as guides, and a smaller protein size. This review provides a comprehensive overview of pAgo protein detection platforms and critically assesses their potential in the field of viral POC diagnostics. The objective is to catalyze further research and innovation in pAgo nucleic acid detection and diagnostics, ultimately facilitating the creation of enhanced diagnostic tools for clinic viral infections in POC settings.

Osteoclast over-activation leads to bone loss and chloride homeostasis is important for osteoclast function. Here, the authors show that Anoctamin 1 controls bone resorption by coupling Cl− channel activation with RANKL-RANK signaling transduction.

Abstract Pulse injection can reduce the maximum operating pressure at the wellhead, which is conducive to solving the operational difficulties caused by the high breakdown pressure. The new injection mode causes a transient fluid flow in the tubing, and it interacts with the initiation and propagation of hydraulic fractures. However, there is still a lack of theoretical models to consider the above factors so that its mechanism cannot be explained. In this study, the transient flow model in the tubing was first established. Subsequently, the fracture propagation model was completed based on particle flow code (PFC). Moreover, the transient flow model was embedded into the PFC simulation software via its code script FISH. Finally, their coupled simulation model was established. Based on this model, the effects of injection flow rates on the fluid pressure in the tubing and the initiation and propagation of hydraulic fractures were discussed. Furthermore, the influence of parameters in the pulse injection scheme on the maximum wellhead pressure was studied by the orthogonal design method. The results show that with the increase of the injection flow rate, the fluid pressurization rate in the tubing and the fracture propagation rate both raise, which also causes a significant increase of the maximum wellhead pressure. Compared with a stable injection mode, pulse injection can evidently reduce the maximum wellhead pressure. The influence degree of each parameter on the maximum wellhead pressure in the pulse scheme is as follows: t2 > Δq > Δt4 > Δt5 > Δt3. The research results of this paper have guiding significance for the engineering application and parameter design of pulse injection hydraulic fracturing.

The inorganic fractions of biochar are influenced by feedstock and pyrolysis conditions. They act as plant nutrients but can also be harmful to the environment. Pyrolysis alters the content and availability of nutrients, including nitrogen, phosphorus, and potassium. Biochars contain trace elements, such as calcium, magnesium, sulfur, and silicon as well as heavy metals. We consider the sources of heavy metals in biochar and their bioavailability, focusing on ensuring agricultural application safety. Biochar-derived nanoparticles can transport inorganic compounds, posing environmental threats. Balancing positive contributions while minimizing the negative impacts of inorganic fractions is essential for optimizing agronomic benefits with biochar.

Summary: Highway constructions on the Qinghai-Tibet Plateau (QTP) face great challenges induced by the unique local environmental, geological, and engineering conditions. The large area of permafrost, great temperature variability, strong UV rays, and complex geological conditions are the major factors that adversely influence the long-term performance of pavement systems. Since 1960s, Chinese engineers and researchers have started conducting research on the QTP to enhance the performance and durability of pavement systems. The present paper provide a comprehensive review of challenge, research and practice of highway constructions on the QTP including the special environmental and geological conditions, history of highway constructions on the QTP, major challenges and the state-of-the-art technology of subgrade constructions on permafrost, developments of the pavement structures and materials, performance prediction and maintenance methods of pavement surfaces, and applications of the research achievements on the first expressway on the QTP (i.e., Gongyu Expressway). Based on the comprehensive literature review, it can be found that (1) frost heave and thaw weakening induced subgrade disease and longitudinal cracks on the pavement surface are complex coupled water-thermal-load problems. Engineering solutions are focusing on active cooling and thermal insulation methods, which can help to reduce temperature variations in the subgrade and thus improving its stability, (2) the harsh environmental and construction conditions may reduce the early strength and induce premature damage of cement-treated base materials. Some field validations showed that geocell-reinforced or asphalt-treated flexible base materials can provide better long-term performance, (3) the large temperature variability and strong UV rays can significantly accelerate aging of asphalt binders and greatly reduce the service life of asphalt mixtures. Various binder modification methods were developed for improving their viscoelasticity and enhance the low-temperature cracking resistance of pavement surface materials but are still lack of field validation data and comparisons of their life cycle costs. Therefore, it is recommended that a demonstration research project build test sections to examine a range of pavement structures and materials, and compare their long-term performance and life cycle costs, which can serve as important reference for future highway constructions on the QTP.

Abstract Background Previous cluster-randomized controlled trials evaluating the impact of implementing evidence-based guidelines for nutrition therapy in critical illness do not consistently demonstrate patient benefits. A large-scale, sufficiently powered study is therefore warranted to ascertain the effects of guideline implementation on patient-centered outcomes. Methods We conducted a multicenter, cluster-randomized, parallel-controlled trial in intensive care units (ICUs) across China. We developed an evidence-based feeding guideline. ICUs randomly allocated to the guideline group formed a local "intervention team", which actively implemented the guideline using standardized educational materials, a graphical feeding protocol, and live online education outreach meetings conducted by members of the study management committee. ICUs assigned to the control group remained unaware of the guideline content. All ICUs enrolled patients who were expected to stay in the ICU longer than seven days. The primary outcome was all-cause mortality within 28 days of enrollment. Results Forty-eight ICUs were randomized to the guideline group and 49 to the control group. From March 2018 to July 2019, the guideline ICUs enrolled 1399 patients, and the control ICUs enrolled 1373 patients. Implementation of the guideline resulted in significantly earlier EN initiation (1.20 vs. 1.55 mean days to initiation of EN; difference − 0.40 [95% CI − 0.71 to − 0.09]; P = 0.01) and delayed PN initiation (1.29 vs. 0.80 mean days to start of PN; difference 1.06 [95% CI 0.44 to 1.67]; P = 0.001). There was no significant difference in 28-day mortality (14.2% vs. 15.2%; difference − 1.6% [95% CI − 4.3% to 1.2%]; P = 0.42) between groups. Conclusions In this large-scale, multicenter trial, active implementation of an evidence-based feeding guideline reduced the time to commencement of EN and overall PN use but did not translate to a reduction in mortality from critical illness. Trial registration: ISRCTN, ISRCTN12233792 . Registered November 20th, 2017.

Lanzhou is the only provincial capital city in Northwest China where the main stream of the Yellow River and its tributaries flow through the city. Due to its geographical location and the influence of various factors, it is difficult to evaluate and simulate the climatic, hydrological, and ecological processes of the main stream of the Yellow River and its tributaries in the region. In this study, the Wanchuan River basin, currently undergoing ecological restoration, was selected as the study area. Seasonal backscatter differences generated using Sentinel-1/2 (S1/S2) data and the CD algorithm were used to reduce the effects of surface roughness; vegetation indices, soils, and field measurements were used to jointly characterize the vegetation contribution and soil contribution. Then, SM maps with a grid spacing of 10 m × 10 m were generated in the Wanchuan River basin, covering an area of 1767.78 km2. To validate the results, optimal factors were selected, and a training set and validation set were constructed. The results indicated a high level of the coefficient of determination (R2) of 0.78 and the root mean square error (RMSE) of 0.08 for the comparison of measured and inverted water contents, indicating that the algorithm retrieved the SM values of the study area well. Furthermore, Box line plots with ERA5-Land and GLDAS confirmed that the algorithm is in good agreement with current SM products and feasibility for soil water content inversion work in the Wanchuan River basin.

Aiming at the problem of poor detection performance under the environment of imbalanced type distribution, an intrusion detection model of genetic algorithm to optimize weighted extreme learning machine based on stratified cross-validation (SCV-GA-WELM) is proposed. In order to solve the problem of imbalanced data types in cross-validation subsets, SCV is used to ensure that the data distribution in all subsets is consistent, thus avoiding model over-fitting. The traditional fitness function cannot solve the problem of small sample classification well. By designing a weighted fitness function and giving high weight to small sample data, the performance of the model can be effectively improved in the environment of imbalanced type distribution. The experimental results show that this model is superior to other intrusion detection models in recall and McNemar hypothesis test. In addition, the recall of the model for small sample data is higher, reaching 91.5% and 95.1%, respectively. This shows that it can effectively detect intrusions in an environment with imbalanced type distribution. Therefore, the model has practical application value in the field of intrusion detection, and can be used to improve the performance of intrusion detection systems in the actual environment. This method has a wide application prospect, such as network security, industrial control system, and power system.

Auricularia auricula is a traditional medicinal and edible mushroom with anti-aging effects. Many studies focused on polysaccharides and melanin. However, the anti-aging effects and mechanism of the nutritional supplementation of Auricularia auricula peptides (AAPs) were not elucidated. In this study, AAPs were prepared by enzymolysis of flavor protease and the protective effects on H2O2-induced senescence of HepG2 cells were explored for the first time. The potential mechanism was also investigated. AAPs were mostly composed of low molecular weights with less than 1000 Da accounting for about 79.17%, and contained comprehensive amino acids nutritionally, including seven essential amino acids, aromatic, acidic, and basic amino acids. AAPs nutritional supplementation could significantly decrease the levels of intracellular reactive oxygen species (ROS) and malondialdehyde (MDA), and increase the activities of antioxidant enzymes (SOD, CAT, and GSH-Px). In addition, the senescence-associated-β-galactosidase (SA-β-gal) activity was restrained, and the expression levels of senescence-associated secretory phenotype (SASP) (IL-6, IL-8, IL-1β, and CXCL2) were also decreased. Ribonucleic acid sequencing (RNA-Seq) was carried out to screen the differentially expressed genes (DEGs) between different groups. GO and KEGG enrichment analysis showed that the mechanism was related to the MAPK/NF-κB signaling pathways. Quantitative real-time PCR (qRT-PCR) analysis and Western blot were carried out to verify the key genes and proteins in the pathways, respectively. AAPs nutritional supplementation resulted a significant down-regulation in key the genes c-fos and c-jun and up-regulation in DUSP1 of the MAPK signaling pathway, and down-regulation in the key genes CXCL2 and IL-8 of the NF-κB signaling pathway. The results of Western blot demonstrate that AAPs nutritional supplementation could inhibit MAPK/NF-κB pathways by reducing the expression levels of IKK, IκB, P65, and phosphorylation of ERK, thus decreasing the inflammatory reaction and delaying cell senescence. It is the first time that AAPs nutritional supplementation was proved to have protective effects on H2O2-induced oxidative damage in HepG2 cells. These results implicate that dietary AAPs could be used as nutrients to reduce the development or severity of aging.

Mushroom bioactive peptides (MBPs) are bioactive peptides extracted directly or indirectly from edible mushrooms. MBPs are known to have antioxidant, anti-aging, antibacterial, anti-inflammatory and anti-hypertensive properties, and facilitate memory and cognitive improvement, antitumour and anti-diabetes activities, and cholesterol reduction. MBPs exert antioxidant and anti-inflammatory effects by regulating the MAPK, Keap1-Nrf2-ARE, NF-κB and TNF pathways. In addition, MBPs exert antibacterial, anti-tumour and anti-inflammatory effects by stimulating the proliferation of macrophages. The bioactivities of MBPs are closely related to their molecular weights, charge, amino acid compositions and amino acid sequences. Compared with animal-derived peptides, MBPs are ideal raw materials for healthy and functional products with the advantages of their abundance of resources, safety, low price, and easy-to-achieve large-scale production of valuable nutrients for health maintenance and disease prevention. In this review, the preparation, bioactivities, mechanisms and structure–activity relationships of MBPs were described. The main challenges and prospects of their application in functional products were also discussed. This review aimed to provide a comprehensive perspective of MBPs.

Abstract Low-resolution electron density maps can pose a major obstacle in the determination and use of protein structures. Herein, we describe a novel method, called quality assessment based on an electron density map (QAEmap), which evaluates local protein structures determined by X-ray crystallography and could be applied to correct structural errors using low-resolution maps. QAEmap uses a three-dimensional deep convolutional neural network with electron density maps and their corresponding coordinates as input and predicts the correlation between the local structure and putative high-resolution experimental electron density map. This correlation could be used as a metric to modify the structure. Further, we propose that this method may be applied to evaluate ligand binding, which can be difficult to determine at low resolution.

Abstract Long non-coding RNA (lncRNA) is a prognostic biomarker for many types of cancer. Here, we aimed to study the prognostic value of lncRNA in Breast Invasive Carcinoma (BRCA). We downloaded expression profiles from The Cancer Genome Atlas (TCGA) datasets. Subsequently, we screened the differentially expressed genes between normal tissues and tumor tissues. Univariate Cox, LASSO regression, and multivariate Cox regression analysis were used to construct a lncRNA prognostic model. Finally, a nomogram based on the lncRNAs model was developed, and weighted gene co-expression network analysis (WGCNA) was used to predict mRNAs related to the model, and to perform function and pathway enrichment. We constructed a 6-lncRNA prognostic model. Univariate and multivariate Cox regression analysis showed that the 6-lncRNA model could be used as an independent prognostic factor for BRCA patients. We developed a nomogram based on the lncRNAs model and age, and showed good performance in predicting the survival rates of BRCA patients. Also, functional pathway enrichment analysis showed that genes related to the model were enriched in cell cycle-related pathways. Tumor immune infiltration analysis showed that the types of immune cells and their expression levels in the high-risk group were significantly different from those in the low-risk group. In general, the 6-lncRNA prognostic model and nomogram could be used as a practical and reliable prognostic tool for invasive breast cancer.

Soil water–salt variations at different spatiotemporal scales and their influencing factors are essential for regional vegetation restoration and management. However, the study of soil water–salt of the alpine area has not taken into account the effect of topography, especially in the long time series. This work investigated the spatiotemporal characteristics of water and salt in topsoil from 2000 to 2021, using regression analysis of on-site data and MODIS products. The heterogeneity and trends of soil water–salt in various topographic factors (elevation, slope, and aspect) were also explored by selecting the maximum area of each gradient factor as the constrained condition with the help of ArcGIS software. The results revealed that 1) the models applied to SWC (soil water content), EC (electrical conductivity), and pH utilizing vegetation indices were suitable for estimating the spatiotemporal variations of soil water–salt. 2) Soil water–salt exhibited local aggregation characteristics with an upward trend in SWC and a downward trend in EC and pH as a whole. 3) Mean annual SWC peaked at 3,400–3,800 m with increasing elevation and trended downward with increasing slope. The aspect of mean annual SWC was characterized by lower values in the southwest and south and higher values in the north, while the results for pH were reversed. The slope had a greater influence on EC than on SWC and pH. 4) The trend change of SWC, EC, and pH fluctuated at 2000–2,400 m and >4,600 m with a clear inflection point at 4°–8° and 20°–24°, respectively. In summary, the effects of topography responded to the distribution and trends of soil water–salt. The results have significant implications for implementing ecological improvements in regions with complicated topography and can serve as a reference for formulating future ecological policies.

B-box (BBX) proteins are one of the zinc-finger transcription factor that plays a critical role in plant development, growth, and multiple stress responses. Although BBX genes have been reported in many model organisms, no comprehensive study has yet been conducted on the BBX genes in Melilotus albus, and the biological functions of this family remain unknown. In this study, a total of 20 BBX (MaBBX) genes were identified in M. albus and were phylogenetically divided into five clades. BBX members within the same clade showed similar conserved domain, suggesting similarity of potential biological function. Analysis of MaBBX conserved motifs showed that every subfamily contained two common motifs. Distribution mapping shows that BBX proteins are nonrandomly localized in eight chromosomes. The synteny showed that most homologous gene pairs of the MaBBX gene family were amplified by segmental replication, which meant segmental replication was the main way for the MaBBX gene family to evolve. Additionally, the cis-element analysis predicted light-responsive, various hormone and stress-related elements in the promoter regions of MaBBXs. Furthermore, the expression levels of all 20 MaBBX genes were detected by qRT-PCR under salt, cold, and dark stresses in M. albus. Moreover, it was observed that 16 genes had higher expression levels after 3 h of salt treatment, 10 genes were significantly upregulated after 3 h of cold treatment, and all genes were up regulated after 3 h of dark treatment, and then appeared to decline. In addition, it was also noticed that MaBBX13 may be an important candidate for improving tolerance to abiotic stress. The prediction of protein tertiary structure showed that the tertiary structures of members of the same subfamily of MaBBX proteins were highly similar. The hypothesis exhibited that most of the MaBBX proteins were predicted to be localized to the nucleus and cytoplasm and was validated by transient expression assays of MaBBX15 in tobacco leaf epidermal cells. This study provides useful information for further investigating and researching the regulatory mechanisms of BBX family genes in response to abiotic stresses in M. albus.

Genome instability is a hallmark of cancer, and the function of lncRNAs in regulating genomic stability has been gradually characterized. However, the prognostic value of lncRNAs related to genetic instability has not been found in breast cancer. Here we constructed a genetic instability-related lncRNA model including U62317.4, SEMA3B-AS1, MAPT-AS1, AC115837.2, LINC01269, AL645608.7, and GACAT2. This model can evaluate the risk and predict the survival outcomes of patients. Further analysis showed that the differentially expressed genes between the high- and low-risk groups were enriched in immunity and cornified envelope formation pathways. In addition, M2 macrophages infiltrated more obviously in the high-risk group. In summary, lncRNAs related to genetic instability may influence the development of breast cancer through immune infiltration and keratinization. This study provides a wider insight into breast cancer development and treatment.

DBC1 has been characterized as a key regulator of physiological and pathophysiological activities, such as DNA damage, senescence, and tumorigenesis. However, the mechanism by which the functional stability of DBC1 is regulated has yet to be elucidated. Here, we report that the ubiquitination-mediated degradation of DBC1 is regulated by the E3 ubiquitin ligase SIAH2 and deubiquitinase OTUD5 under hypoxic stress. Mechanistically, hypoxia promoted DBC1 to interact with SIAH2 but not OTUD5, resulting in the ubiquitination and subsequent degradation of DBC1 through the ubiquitin–proteasome pathway. SIAH2 knockout inhibited tumor cell proliferation and migration, which could be rescued by double knockout of SIAH2/CCAR2. Human tissue microarray analysis further revealed that the SIAH2/DBC1 axis was responsible for tumor progression under hypoxic stress. These findings define a key role of the hypoxia-mediated SIAH2-DBC1 pathway in the progression of human breast cancer and provide novel insights into the metastatic mechanism of breast cancer.

Decaprenyl diphosphate synthase subunit 1 (PDSS1) is closely related to a variety of human diseases, but its expression pattern and biological function in HCC have not been studied to date.MethodsThe expression level of PDSS1 was analyzed using the TCGA and GEO databases. The relationships between PDSS1 and patient clinicopathological characteristics were verified based on TCGA clinical data. Additionally, the co-expressed genes of PDSS1were investigated and Gene Set Enrichment Analysis (GSEA) was conducted using LinkedOmics. Next, the association between PDSS1 and immune infiltration was determined using version 1.34.0 of the GSVA package. EdU assay, colony-formation assay, transwell assay, wound-healing assay, and flow cytometry analysis were used to assess the effect of PDSS1 on the cell phenotype.ResultsPDSS1 was upregulated in HCC compared with adjacent tissues. High PDSS1 in HCC was associated with poor overall survival, disease-specific survival, and progress-free interval. Results suggested that PDSS1 may activate multiple oncogenic pathways in HCC, especially those involved in the cell cycle. The expression of PDSS1 was significantly related to Th2 cells, TFH, T helper cells, NK CD56bright cells, cytotoxic cells, DC, CD8 T cells, and neutrophils. PDSS1 knockdown inhibited cell proliferation, cell cycle, migration and invasion. Furthermore, PDSS1 acted as an oncogene through the STAT3 signaling pathway.ConclusionOur study reveals that a high level of PDSS1 is significantly correlated with poor patient prognosis and immune cell infiltration in HCC. PDSS1 may be a novel biomarker and potential therapeutic target for HCC.

The wellbore of a sucker-rod pumping well experiences a multi-phase flow consisting of oil, gas, and water. The flow pattern and pump discharge pressure are greatly impacted by oil well production, which in turn significantly affects the simulation results of longitudinal vibration in the sucker-rod string. When calculating the discharge pressure in a hydrostatic column containing both oil and water (HC), the pressure is not affected by the oil well’s production. This thereby avoids interference between vibrations in the sucker-rod string’s longitudinal direction and the flow from the wellbore. Considering the coupling characteristics between the longitudinal vibration of the sucker-rod string and the wellbore flow, a mathematical model of the sucker-rod pumping system (CMSRS) and a mathematical model of the downhole energy efficiency parameters were established. In detail, the CMSRS comprises two parts: the discharge pressure mathematical models of multi-phase flow dynamics (MD) and the wave equation of the longitudinal vibration of the sucker-rod string. A numerical simulation model of the sucker-rod pumping system was constructed based on a mathematical model. We compared the experimental results, the simulation results of the CMSRS and the simulation results of the sucker-rod string based on the oil-water two–phase hydrostatic column (SMSRS) and found good agreement, indicating the feasibility of the CMSRS. The simulation details show the following: (1) The HC model’s discharge pressure exceeds that of the MD model by more than 33.52%. The polished rod load for the CMSRS is 18.01% lower than that of the SMSRS, and the pump input power for the CMSRS is 36.23% lower than that of the SMSRS. (2) The effective power simulation model based on the energy balance relationship is essentially the same as the effective power calculated by the model based on multi-phase flow effective power. This validates the accuracy of the multi-phase flow effective power model. (3) The limitations of the industry standard effective power model are that (i) the effective head is the net lift height of the fluid in the wellbore reduced to the oil and water phases rather than the effective lift height based on the energy balance relationship and (ii) the power of the gas phase delivered by the pumping pump is disregarded, and only the effective power of the pump delivering the oil-water mixture is considered. (4) The influence of the wellbore parameters on the wellbore efficiency and sub–efficiency is systematically analyzed. The analysis results have an important significance in the guidance of energy saving in pumping wells.

The five recognized zoonotic foodborne pathogens, namely, Listeria monocytogenes, Staphylococcus aureus, Streptococcus suis, Salmonella enterica and Escherichia coli O157:H7, pose a major threat to global health and social–economic development. These pathogenic bacteria can cause human and animal diseases through foodborne transmission and environmental contamination. Rapid and sensitive detection for pathogens is particularly important for the effective prevention of zoonotic infections. In this study, rapid and visual europium nanoparticle (EuNP)-based lateral flow strip biosensors (LFSBs) combined with recombinase polymerase amplification (RPA) were developed for the simultaneous quantitative detection of five foodborne pathogenic bacteria. Multiple T lines were designed in a single test strip for increasing the detection throughput. After optimizing the key parameters, the single-tube amplified reaction was completed within 15 min at 37 °C. The fluorescent strip reader recorded the intensity signals from the lateral flow strip and converted the data into a T/C value for quantification measurement. The sensitivity of the quintuple RPA-EuNP-LFSBs reached a level of 101 CFU/mL. It also exhibited good specificity and there was no cross-reaction with 20 non-target pathogens. In artificial contamination experiments, the recovery rate of the quintuple RPA-EuNP-LFSBs was 90.6–101.6%, and the results were consistent with those of the culture method. In summary, the ultrasensitive bacterial LFSBs described in this study have the potential for widespread application in resource-poor areas. The study also provides insights in respect to multiple detection in the field.

Porcine epidemic diarrhea virus (PEDV), porcine bocavirus (PBoV), and porcine rotavirus (PoRV) are associated with porcine viral diarrhea. In this study, triplex loop-mediated isothermal amplification (LAMP) combined with a lateral flow dipstick (LFD) was established for the simultaneous detection of PEDV, PoRV, and PBoV. The PEDV-gp6, PoRV-vp6, and PBoV-vp1 genes were selected to design LAMP primers. The amplification could be carried out at 64 °C using a miniature metal bath within 30 min. The triplex LAMP–LFD assay exhibited no cross-reactions with other porcine pathogens. The limits of detection (LODs) of PEDV, PoRV, and PBoV were 2.40 × 101 copies/μL, 2.89 × 101 copies/μL, and 2.52 × 101 copies/μL, respectively. The consistency between rt-qPCR and the triplex LAMP–LFD was over 99% in field samples testing. In general, the triplex LAMP–LFD assay was suitable for the rapid and simultaneous detection of the three viruses in the field.

Drug abuse is becoming increasingly dangerous nowadays. Morphine (MOP), methamphetamine (MET) and ketamine (KET) are the most commonly abused drugs. The abuse of these drugs without supervision can cause serious harm to the human body and also endanger public safety. Developing a rapid and accurate method to screen drug suspects and thus control these drugs is essential to public safety. This paper presents a method for the simultaneous quantitative detection of these three drugs in hair by a europium nanoparticles-based fluorescence immunochromatographic assay (EuNPs−FIA). In our study, the test area of the nitrocellulose membrane was composed of three equally spaced detection lines and a quality control line. The test strip realized the quantitative analysis of the samples by detecting the fluorescence brightness of the europium nanoparticles captured on the test line within 15 min. For the triple test strip, the limits of detection of MOP, KET and MET were 0.219, 0.079 and 0.329 ng/mL, respectively. At the same time, it also showed strong specificity. The strip was stable and could be stored at room temperature for up to one year, and the average recovery rate was 85.98–115.92%. In addition, the EuNPs−FIA was validated by high-performance liquid chromatography (HPLC) analysis, and a satisfactory consistency was obtained. Compared to the current immunochromatographic methods used for detecting abused drugs in hair, this method not only increased the number of detection targets, but also ensured sensitivity, improving detection efficiency to a certain extent. The approach can also be used as an alternative to chromatography. It provides a rapid and accurate screening method for the detection of abused drugs in hair and has great application prospects in regard to public safety.

The compression molding performance of a substrate block has a significant effect on the quality and stability of mechanical transplanting. The physical experiment and DEM simulation were combined to evaluate the compression molding behavior of substrate block in this study. A calibration procedure of DEM parameters of peat particles was proposed at first. Then, the above parameters were brought into the contact model of the compression system–particles, and the effect of the loading speed on the compression behavior of the peat substrate block was investigated. The compressive force–displacement curves of the simulated and measured tests were all contained in the initial linear stage and non-linear stiffing stage. The particle number of central sections was higher than side section, and the variable coefficient was greater at higher loading speed. The substrate blocks all expanded after demolding. The higher the loading speed, the greater the expansion in the height’s direction, and the easier it was for cracks to be generated near the bottom. This study will provide a reference for the design of substrate block forming machines.

The diffusion of e-commerce has played a significant role in recent rural economic development in China. E-commerce is also considered as an efficient channel to alleviate poverty in rural China. Voluminous studies have investigated the contribution of e-commerce to agricultural development, yet it is lacking empirical evidence as to the effects of e-commerce on rural poverty alleviation. Since the year of 2014, in order to develop rural e-commerce, Chinese government launched the National Rural E-commerce Comprehensive Demonstration Project. This gradual involvement policy offered a natural experiment for evaluation of e-commerce. Based on village-level survey data from rural China and Heckit method, our study finds that rural e-commerce has a significantly positive effect on rural income. Moreover, the effect is inverted U-shaped for the relative-poverty villages. The estimation of the propensity scores matching model confirms that the results are robust. The following policy recommendations are proposed: (1) policy support to rural e-commerce should prioritize the poverty-stricken villages. By doing so, the marginal income effects of e-commerce will be maximized. (2) Investment in internet infrastructure and establishment of human resources for e-commerce in rural areas will have spillover effects, increasing rural income through the “digital dividend”.

Abstract Approximately 15–30% of patients with lung cancer harbor mutations in the EGFR gene. Major EGFR mutations (>90% of EGFR-mutated lung cancer) are highly sensitive to EGFR tyrosine kinase inhibitors (TKIs). Many uncommon EGFR mutations have been identified, but little is known regarding their characteristics, activation, and sensitivity to various EGFR-TKIs, including allosteric inhibitors. We encountered a case harboring an EGFR-L747P mutation, originally misdiagnosed with EGFR-del19 mutation using a routine diagnostic EGFR mutation test, which was resistant to EGFR-TKI gefitinib. Using this minor mutation and common EGFR-activating mutations, we performed the binding free energy calculations and microsecond-timescale molecular dynamic (MD) simulations, revealing that the L747P mutation considerably stabilizes the active conformation through a salt-bridge formation between K745 and E762. We further revealed why several EGFR inhibitors, including the allosteric inhibitor, were ineffective. Our computational structural analysis strategy would be beneficial for future drug development targeting the EGFR minor mutations.

ABSTRACT To accurately measure sowing depth, we designed a multisensor data fusion algorithm based on the Kalman filter and applied it to a dual-channel ultrasonic sowing depth measurement system. We installed two ultrasonic sensors on the frame above the depth limit wheel and the soil covering-compacting wheel. The terrain-like plate was installed on the central axis of the depth limit wheel to simulate the surface relief and calculate the seeding depth value. The Kalman filter algorithm filters out the clutter generated when the two ultrasonic sensors collect the depth data and then fuses the two ultrasounds of the filtered data. The test shows that when the vehicle speed is 4 km/h , the fluctuation ranges of the collected data of ultrasonic 1 and 2 are 45-60 mm and 35-70 mm , respectively, and the fluctuation ranges of the filtered data are 52-58 mm and 48-60 mm , respectively. After data fusion processing, the data fluctuate in a small range of approximately 55 mm . When the vehicle speed is 6 km/h and 8 km/h, the obtained results have the same trend as the experimental results at 4 km/h . The results show that the sowing depth measurement system is effective.

Resistance to ALK inhibitors such as lorlatinib often arise due to on-target mutations. Here, the authors show the multi-kinase inhibitor gilteritinib is effective against different mutations that arise during lorlatinib in ALK fusion positive lung cancer to cause resistance.