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Osimertinib (AZD9291) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), used for treating patients with advanced non-small-cell lung cancer (NSCLC) harboring EGFR-activating mutations or the resistant T790M mutation. However, acquired resistance to osimertinib is inevitable in EGFR-mutant NSCLC. By employing a global mass spectrometry-based phosphoproteomics approach, we identified that the activated p21-activated kinase 2 (PAK2)/β-catenin axis acts as a driver of osimertinib resistance. We found that PAK2 directly phosphorylates β-catenin and increases the nuclear localization of β-catenin, leading to the increased expression and transcriptional activity of β-catenin, which in turn enhances cancer stem-like properties and osimertinib resistance. Moreover, we revealed that HER3 as an upstream regulator of PAK2, drives the activation of PAK2/β-catenin pathways in osimertinib-resistant cells. The clinical relevance of these findings was further confirmed by examining tissue specimens from patients with EGFR-mutant NSCLC. The results demonstrated that the levels of HER3, phospho-PAK2 (p-PAK2) and β-catenin in the tissues from patients with EGFR-mutant NSCLC, that had relapsed after treatment with osimertinib, were elevated compared to those of the corresponding untreated tissues. Additionally, the high levels of HER3, p-PAK2 and β-catenin correlated with shorter progression-free survival (PFS) in patients with EGFR-TKI-treated NSCLC. We additionally observed that the suppression of PAK2 via knockdown or pharmacological targeting with PAK inhibitors markedly restored the response of osimertinib-resistant NSCLC cells to osimertinib both in vitro and in vivo. In conclusion, these results indicated that the PAK2-mediated activation of β-catenin is important for osimertinib resistance and targeting the HER3/PAK2/β-catenin pathway has potential therapeutic value in NSCLCs with acquired resistance to osimertinib.

Increasing evidences suggest that mitochondrial dysfunction is implicated in diseases and aging, and whole-genome sequencing (WGS) is the most unbiased method in analyzing the mitochondrial genome (mtDNA). However, the genetic landscape of mtDNA in the Chinese population has not been fully examined. Here, we described the genetic landscape of mtDNA using WGS data from Chinese individuals (n = 3241). We identified 3892 mtDNA variants, of which 3349 (86%) were rare variants. Interestingly, we observed a trend toward extreme heterogeneity of mtDNA variants. Our study observed a distinct purifying selection on mtDNA, which inhibits the accumulation of harmful heteroplasmies at the individual level: (1) mitochondrial dN/dS ratios were much

A proportion of previously defined benign variants or variants of uncertain significance in humans, which are challenging to identify, may induce an abnormal splicing process. An increasing number of methods have been developed to predict splicing variants, but their performance has not been completely evaluated using independent benchmarks. Here, we manually sourced ∼50 000 positive/negative splicing variants from > 8000 studies and selected the independent splicing variants to evaluate the performance of prediction methods. These methods showed different performances in recognizing splicing variants in donor and acceptor regions, reminiscent of different weight coefficient applications to predict novel splicing variants. Of these methods, 66.67% exhibited higher specificities than sensitivities, suggesting that more moderate cut-off values are necessary to distinguish splicing variants. Moreover, the high correlation and consistent prediction ratio validated the feasibility of integration of the splicing prediction method in identifying splicing variants. We developed a splicing analytics platform called SPCards, which curates splicing variants from publications and predicts splicing scores of variants in genomes. SPCards also offers variant-level and gene-level annotation information, including allele frequency, non-synonymous prediction and comprehensive functional information. SPCards is suitable for high-throughput genetic identification of splicing variants, particularly those located in non-canonical splicing regions.

Graphical abstract, Folate deficiency is an environmental risk factor for several developmental disorders. De novo mutations (DNMs) also play important etiological roles in various developmental disorders. However, it remains unclear whether DNMs in folate-related genes (FRGs) contribute to developmental disorders. We obtained a list of 1,821 FRGs from folate metabolism pathways and the Comparative Toxicogenomics Database, along with data concerning DNMs in 15,404 cases and 3,391 controls from the Gene4Denovo database. We used a TADA-Denovo model to prioritize candidate disease-associated FRGs, and characterized these genes in terms of genic intolerance, functional networks, and expression patterns. Compared with the controls, FRGs were significantly enriched in likely damaging DNMs (ldDNMs) in patients with developmental disorders (1.54 ≤ odds ratio ≤ 3.39, Padj ≤ 0.0075). Furthermore, FRGs with ldDNMs rather than with likely non-damaging DNMs (lndDNMs) overlapped significantly among the five developmental disorders included in the datasets. The TADA-Denovo model prioritized 96 candidate disease-associated FRGs, which were intolerant to genetic variants. Their functional networks mainly involved pathways associated with chromatin modification, organ development, and signal transduction pathways. DNMT3A, KMT2B, KMT2C, and YY1 emerged as hub FRGs from the protein–protein interaction network. These candidate disease-associated FRGs are preferentially expressed in the excitatory neurones during embryonic development, and in the cortex, cerebellum, striatum, and amygdala during foetal development. Overall, these findings show that DNMs in FRGs are associated with the risk of developmental disorders. Further research on these DNMs may facilitate the discovery of developmental disorder biomarkers and therapeutic targets, enabling detailed, personalized, and precise folate treatment plan.

Long single-molecular sequencing, such as PacBio circular consensus sequencing (CCS) and nanopore sequencing, is advantageous in detecting DNA 5-methylcytosine (5mC) in CpGs, especially in repetitive genomic regions. However, existing methods for detecting 5mCpGs using PacBio CCS are less accurate and robust. Here, we present ccsmeth, a deep-learning method to detect DNA 5mCpGs using CCS reads. We sequence PCR-treated and M.SssI-treated DNA of one human sample using PacBio CCS for training ccsmeth. Using long (≥10Kb) CCS reads, ccsmeth achieves 0.90 accuracy and 0.97 AUC on 5mCpG detection at single-molecule resolution. At the genome-wide site level, ccsmeth achieves >0.90 correlations with bisulfite sequencing and nanopore sequencing using only 10× reads. Furthermore, we develop a Nextflow pipeline, ccsmethphase, to detect haplotype-aware methylation using CCS reads, and then sequence a Chinese family trio to validate it. ccsmeth and ccsmethphase can be robust and accurate tools for detecting DNA 5mCs using PacBio CCS.

In recent years, tidal current power generation technology has achieved rapid development. On the basis of summarizing the characteristics of tidal current power generation, this paper comprehensively analyzes the distribution law of electric energy in tidal current power generation. Hilbert huang transform was applied to the trend of energy in power quality detection and analysis, the key can power on the trend of the measured data grouping processing, and carried out in accordance with the time period, such as day, month and year of HHT analysis, can get tide power distribution, can verify the HHT analysis in the trend of the power law research in the application feasibility and accuracy.

Direct loading test are the general test method to obtain running performance of induction motors. However, direct loading test is difficult to test cryogenic induction motors for submerged liquefied natural gas (-162°C, LNG) pumps because the motors are installed inside the LNG pumps and share the shaft with the pump. This paper presents a semi-static methodology that can successfully predict the running performance of a 15kW cryogenic induction motor for LNG pumps. The methodology combines a static double-frequency test with a rotating no-load test, based on a Г-equivalent circuit model, to calculate the running performance of the 15kW motor in liquid nitrogen (-196°C, LN). Experimental validation of the methodology is provided by direct loading test in LN. Finally, the methodology is used to predict the performance of the motor in LNG.

When tidal current energy generation is connected to the grid with distributed energy or directly applied to the equipment, it is necessary to detect the power quality of tidal current energy to avoid grid operation failure or damage to precision equipment. In this paper, the principle of tidal current energy generation is introduced, and the problem of power quality is analyzed based on Hilbert Huang transform(HHT). The Hilbert spectrum is obtained by Empirical Mode Decomposition(EMD) and Hilbert transform. The results show that HHT can detect the harmonic and other power quality problems in power system, which is of great significance in the further analysis of quality detection of tidal current energy.

This paper reports on a method for the analysis of a cryogenic induction motor for submerged liquefied natural gas (-162°C, LNG) pumps by coupled electromagnetic and thermal models in commercial software, MotorCAD. Examples using a 15kW cryogenic prototype in LN illustrate the method is an available tool for analyzing the cryogenic motor. Furthermore, the motor performance in LNG is investigated by this tool. This paper will be useful to scholars and engineers interested in cryogenic motors.

Focus on the torque balance control of dual-motor driven system (DMDS), this paper proposes an equivalent switching variable structure sliding mode control (VSSMC) algorithm, which can improve the response speed and anti-interference performance of the system. Comparing with the traditional PI control algorithm, the equivalent switching VSSMC can eliminate the steady-state tracking error completely. Based on two control strategies proposed in the previous study, the simulation analysis of the two algorithms is carried out respectively by using MATLAB in this paper, and the effectiveness of equivalent switching VSSMC algorithm is further verified by the simulation results.

Considering the advantage of safety and cost, designing a Mg–air battery with high capacity has been highly sought in recent years. However, self-corrosion and passivation of Mg anode critically reduce discharge performance, hindering the large-scale application of Mg–air batteries. In this study, a series of as-cast and extruded Mg-3In-xCa alloys were successfully fabricated. Microstructures, chemical composition, and discharge performance were investigated to optimize the content of Ca (x). The selected Mg–air battery with Mg-3In-3Ca alloy as anode represented the best battery performance, including 0.738 V of discharge voltage, 1323.92 mAh g−1 of specific capacity, and 61.74% of anodic efficiency at discharge current density of 30 mA cm−2. All of its parameters were vastly superior to pure Mg–air battery. In addition, the synergistic effects of In and Ca on promoting electrode properties were evaluated in detail, using SEM and electrochemical analysis, which is expected to trigger follow-up research in designing high-performance Mg–air batteries.

Resulting from the rising levels of atmospheric carbon, ocean acidification has become a global problem. It has significant impacts on the development, survival, growth and physiology of marine organisms. Therefore, a high-precision sensor is urgently needed to measure the pH of sea-water. Iridium wire with a diameter of 0.25 mm is used as the substrate, and an Ir/Ir(OH) x pH electrode is prepared by a one-step electrochemical method in a LiOH solution at the room temperature. A scanning electron microscope (SEM) observation reveals that it is coated with nanoscale particles. In laboratory tests, the electrode exhibits a very promising pH response, with an ideal Nernst slope (56.14–59.52), fast response, good stability and long life-span in tested pH buffer solutions. For a sea trial, four pH electrodes and one Ag/AgCl reference electrode are integrated with a self-made chemical sensor, and a profile detection of nearly 70 m is implemented near Newport Harbor, California on August 3, 2015. The results reflect that the pH value measured by the sensor is very close to the data given by Sea-Bird 911 plus CTD, with a difference value ranging from 0.000 075 to 0.064 719. And the sensor shows a better data matching degree in 0–40 m water depth. In addition, the high precision and accuracy of the sensor make it possible to use in the ocean observation field.

In this paper, we successfully fabricated a novel bromide ion selective electrode (Br-ISE), which was coated by bromine ion doped polyaniline as sensitive film. Using Ag wire as the substrate, a uniform and dense nano-silver layer was electroplated to enhance the specific surface area of the electrode. Subsequently, a polyaniline (PANI) film was coated onto the electrode by cyclic voltammetry in a 0.3 M aniline and 1 M HCl solution and was in-situ doped by 0.1 M KBr solution. The morphology and performance of the electrode were characterized by scanning electron microscopy (SEM), electrochemical impedance spectroscopy (EIS), and other electrochemical analysis methods, respectively. The prepared Br-ISE exhibited a wide linear dynamic range between 1.0 &times, 10&minus, 1 and 1.0 &times, 7 M with a near-Nernst slope of 57.33 mV/decade. In addition, the electrode possessed extremely fast response time (&lt, 1 s) and low impedance (300 &Omega, ), high sensitivity, and good selectivity. The electrode potential drifted within 2 mV in 8 h. The lifespan was larger than three months.

Ion-Selective Electrode (ISE) is an emerging technology for in situ monitoring of the chemical concentrations of an aqueous environment. In this work, we reported a novel all-solid-state silicate ISE, using an Ag/Pb/PbSiO3 electrode. This electrode responded to aqueous SiO32− with a reasonable slope of −31.34 mV/decade and a good reproductivity. The linear range covered from 10−5 M to 10−1 M, for the Na2SiO3 solutions and the response time was generally less than 5 s. Its potentiometric response to pH and silicate indicated that the prepared electrode was sensitive to silicate, rather than pH. Compared to the traditional liquid ISE, our all-solid-state silicate electrode was resistant to high pressure and could be used in situ, in deep water. In addition, the miniaturized electrodes (diameter of 0.4 mm and a length of 2⁻3 cm) could be easily integrated into a multi-modal sensor, which could simultaneously determine multiple parameters. Our prepared silicate ISE could potentially be used to determine the presence of silicate in a low-chloride aqueous environment, where the ISE exhibited better selectivity for silicate, over interfering ions such as, SO42−, NO3−, CH3COO−, CO32−, and PO43−.

The Double Motors Drive System (DMDS) is wildly used in production or scientific research areas., and the coordinated control problem of DMDS is the crucial factor determining its development and application. Based on two new control strategies., this paper focused on the torque balance control problem of DMDS., comparatively analyzed the control effects of traditional PI control algorithm and adaptive VSSMC algorithm. Finally., Experiment and simulation results demonstrated that the adaptive VSSMC algorithm could help the system achieve better tracking performance.

The Double Motors Drive System (DMDS) is wildly used in production or scientific research areas, and the coordinated control problem of DMDS is the crucial factor determining its development and application. Based on two new control strategies, this paper focused on the torque balance control problem of DMDS, comparatively analyzed the control effects of traditional PI control algorithm and exponential reaching law Variable Structure Sliding Mode Control (VSSMC) algorithm. Finally, Experiment and simulation results demonstrated that the exponential reaching law VSSMC algorithm could help the system achieve better tracking performance.

A new all-solid-state carbonate ion-selective electrode was fabricated via electrochemical and ion-exchange reactions with Ag nanoparticles and Ag2CO3-BaCO3 as ion-to-electron transducer and ion-selective layer, respectively. This paper presented the detailed procedures of the construction of the electrode, the applications of the electrode in various experiments, and the corresponding chemical reaction principles involved. The fabricated electrode was characterized by means of scanning electron microscopy(SEM), energy dispersive spectrometer(EDS), and electrochemical analyses. The electrode exhibited stable linear responses to carbonate anions(10–5―10–1 mol/L) with average slope of the curve being–26.56 mV per decade, and showed negligible responses to NO 3 – , SO 4 2– , and Sal– anions. The electrode was further used to measure the concentration of carbonate anions in boiler water. The measured concentration was lower than that determined via titration. Overall, the electrode exhibited the advantages of miniaturized size, robust construction, and compatibility with other equipment and thus could be ideally integrated into various sensor platforms to collect chemical data from industrial heat exchangers.

Eutrophication-induced ocean acidification is causing a dramatic ecologic change in the coastal ocean. A more acidic ocean would lead to more volatile H 2 S in the coastal ocean, especially in the area where shallow hydrothermal vents exist. Therefore, the early detection of H 2 S and its associates is needed. In this study, the preparation method for and the detection limit of an Ag/Ag 2 S electrode were optimized by coating the electrode with micro-scale to nano-scale silver particles. The size of the silver particles was dependent on the electroplating power used to produce them: (1) direct current power made micrometer scale silver particles, and (2) direct current carrier power made nano-scale silver particles. As a result, the detection limits of [S 2− ] of the Ag/Ag 2 S electrode made using direct current and direct carrier current were improved to 1×10 −5 mol L −1 and 1×10 −7 mol L −1 , respectively. Such improvements were mostly due to the fact that nano silver particles have larger surface area and higher surface energy. The Ag/Ag 2 S electrode made by direct carrier current method was then mounted to a multi-parameter sensor (including a pH and an Eh electrode) used to search of new hydrothermal vents near the Kueishan Tao in May, 2011. A new hydrothermal vent was discovered based on pH, Eh and H 2 S anomalies at three depths. A clear [S 2− ] signal anomaly was observed from the top sensor indicating the dispersive pattern of the hot fluid near this shallow vent site. This could also provide additional information on the dispersion pattern of anthropogenic pollutants in the coastal ocean.

On account of the GPS initial technology limitations, it is vulnerable to interference, deception and other security attacks; GPS is widely used. If it is attacked, it will bring very serious consequences. Due to the problem of cost, civil GPS seldom considers how to defend against security attack. Therefore, it is necessary to study a fast and efficient GPS deception signal detection method to resist the attack. By improving the existing detection methods of GPS deception signal, a composite detection method of GPS deception signal is proposed. Based on DOA detection, the detection of signal propagation time difference is added, and the existence of GPS deception signal is judged synthetically according to whether the signal angle of arrival and the signal propagation time difference exceed the threshold value of real signal. The improved method improves the detection efficiency by reducing the calculation times of the signal angle of arrival. By reducing the number of detection signals to improve the detection accuracy of signal propagation time difference when there are more detection signals and less deception signals, thus ensuring the accuracy of composite detection. And subsequent simulation experiments successfully detected direct GPS deception signals, which verified the feasibility of this method for rapid detection of direct deception signals.

In this paper, a set of online measurement devices of multi-electrochemical sensor was investigated. Combined with industrial distributed control system, it was first applied in extracting bromine from seawater to realize the real-time adjustment of production process parameters. In the process of extracting bromine from seawater, the pH value of acidified raw brine, the addition amount of Cl 2 in the oxidation stage and the addition amount of SO 2 in the absorption stage are key parameters to control the whole production process. The multi-electrochemical sensor realized a rapid and high-throughput detection of the above parameters by integrating an all-solid-stage bromide ion selective electrode (Br-ISE), Eh electrode and pH electrode. The Br-ISE and the pH electrode were self-developed electrodes and the Pt electrode was Eh electrode. The pH electrode was used to control the addition amount of H 2 SO 4 during the acidification of the brine. The Eh electrode was used to control the addition amount of Cl 2 during the oxidation stage and the addition amount of SO 2 during the absorption stage. The Br-ISE was used to monitor the Br − concentration change in the raw brine. Results showed the optimum range of Eh in the oxidation stage and absorption stage of brine were 950–1000 mV and 580–610 mV, respectively. The application of multi-electrochemical sensor in industrial bromine production can realize real-time control of material addition and save the cost of production.

Hybrid materials based on polyvinyl alcohol (PVA) and mercaptopropyltriethoxysilane (MPTES) with embedded silver nanoparticles (AgNps) have been synthesized via a sol–gel method. Silver nanoparticles were obtained via thermal reduction in the presence of PVA as a stabilizer and reducing agent. The formation of silver nanoparticles within the PVA/MPTES matrix was proven by FTIR, XRD, and TEM analysis. The antibacterial activity of PVA/AgNps/MPTES materials was determined against strains belonging to Gram-positive and Gram-negative bacteria by disk diffusion and growth curve methods. The hybrid materials showed high antibacterial activity, which depends on the concentration of the silver nanoparticles.

Superhydrophobic, water repellent surfaces have attracted much attention but poor surface mechanical properties have limited their wider practical application. Robust surfaces based on nickel-tungsten carbide composite coatings have been electrodeposited. The surfaces showed superhydrophobicity after being modified by stearic acid. The maximum contact angle of water was 164.3 degrees with a sliding angle close to zero degree. By controlling deposition conditions, versatile coatings have been produced and the effects of morphology on wettability are discussed. Coating texture has been analyzed by X-ray diffraction. The surfaces showed excellent abrasion resistance and water-repellence.

Three kinds of commercial silica gels with pore size of 2-3, 4-7 and 8-10 nm respectively are used for preparing composite adsorbents by soaking them into the aqueous solution of calcium chloride. The test result indicates that both the water uptake and adsorption rate of composite adsorbents prepared from 4-7 and 8-10 nm silica gels improve greatly compared to pure silica gels, but they do not for 2-3 nm silica gels. The silica gel with pore size of 2-3 nm is not suitable for preparing the composite adsorbent by impregnation method due to the pore blockage because of the small pore size. The SCP and COP of the adsorption chiller with sample SA50 are 128.3 Wkg(-1) and 0.27 respectively at the hot source temperature of 90 A degrees C, which are largely superior to that of SA0. Hence using the composite adsorbent instead of the pure silica gel can reduce the size of the adsorption chiller.