Novel bioactive 2-phenyl-4-aminopyrimidine derivatives as EGFRDel19/T790M/C797S inhibitors for the treatment of non-small cell lung cancer.

Overexpression of the epidermal growth factor receptor (EGFR) has been implicated in the development of non-small-cell lung cancer (NSCLC). Thus, EGFR is an effective drug target for the treatment of NSCLC, and developing fourth-generation EGFR inhibitors to overcome the resistance mediated by T790M/C797S mutations are currently under investigation. In this study, based on the binding model between Angew2017-7634-1 and EGFRT790M/C797S , several series of 2-phenyl-4-aminopyrimidine derivatives were designed and synthesized. The bioactivity of these compounds was evaluated and it is suggested that compound A23 could effectively inhibit the proliferation of Ba/F3-EGFRDel19/T790M/C797S and H1975-EGFRL858R/T790M cells, with an IC50 of 0.22 ± 0.07 and 0.52 ± 0.03 µM, respectively. Meanwhile, the kinase activity of A23 against EGFRL858R/T790M and EGFRDel19/T790M/C797S was also evaluated, with an IC50 of 0.33 and 0.133 µM, respectively. Moreover, compound A23 was further evaluated in the H1975 xenograft models with significant in vivo tumor growth inhibitions of 25.5%, which means that A23 could effectively inhibit the growth of tumor cells and promote the death of tumor cells. As a result, A23 could be identified as a novel potential EGFRDel19/T790M/C797S inhibitor.

Long-term grazing improved soil chemical properties and benefited community traits under climatic influence in an alpine typical steppe.

Grazing and climate change both contribute to diversity loss and productivity fluctuations. Sensitive climate conditions and long-term grazing activities have a profound influence on community change, particularly in high-altitude mountain grassland ecosystems. However, knowledge about the role of long-term continuous grazing management on diversity, productivity and the regulation mechanisms in fragile grassland ecosystems is still rudimentary. We conducted a long-term grazing experiment on an alpine typical steppe in the Qilian Mountains to assess effects of grazing intensity on soil, diversity, productivity and the regulation mechanisms. Plants and soil were sampled along grazing gradients at different distances from the pasture entrance (0, 0.3, 0.6, 0.9, 1.2 and 1.5 km) under the non-growing (WP) and the growing season grazing pasture (SAP). The results revealed that community diversity and biomass did not change significantly on a time scale, while the concentration of soil organic carbon and total phosphorus increased significantly. Heavy grazing (0-0.3 km) decreased community diversity and biomass. Grazing increased soil chemical properties in heavy grazed areas of WP, while the opposite was recorded in SAP. Soil chemical properties explained the largest variances in community diversity and community biomass. The prediction model indicates that grazing in WP mainly affects community diversity through soil chemical properties, and promotes a positive correlation between community diversity and community biomass; in SAP, the direct effect of grazing gradients on community diversity and biomass is the main pathway, but not eliminating the single positive relationship between diversity and biomass, which means that diversity can still be used as a potential resource to promote productivity improvement. Therefore, we should focus on the regulation of soil chemical properties in WP, such as the health and quality of soil, strengthening its ability to store water, sequester carbon and increase nutrients; focus on the management of livestock in SAP, including providing fertilizer and sowing to increase diversity and production in heavily grazed regions and reducing grazing pressure through regional rotational grazing. Ultimately, we call for strengthening the stability and sustainability of ecosystems through targeted and active human intervention in ecologically sensitive areas to cope with future grazing pressures and climate disturbances.

In silico screening combined with bioactivity evaluation to identify AMI-1 as a novel anticancer compound by targeting AXL.

Recently, some studies have proven that AXL plays a crucial role in the drug resistance of tumors. At present, no AXL inhibitors on the market and it is essential to discover novel compounds targeting AXL to overcome resistance. In this work, based on the anchor structure, 21,313 compounds were obtained by substructure search from more than 400,000 compounds. Then, the Qvina and Ledock were selected for virtual screening to obtain 17 compounds. Next, four compounds (ARRY614, AMI-1, NG25, and Butein) were selected for bioactivity evaluation after hydrogen bond and cluster analysis. Further activity evaluation suggested that the compound AMI-1 is a novel AXL inhibitor with an IC50 value of 1.13 uM. In addition, molecular dynamics simulation demonstrated that compound AMI-1 contained lower binding energy and more key residues than the other three compounds, showing the best inhibitory activity against AXL. Finally, further MM/PBSA prediction showed that AMI-1 is more sensitive to mutant protein 3IKA than wildtype protein 1M17, which means that the AMI-1 may be helpful to overcome the resistance of EGFRT790M mutations. In conclusion, this work successfully discovered a novel compound with moderate inhibitory activity against AXL by a drug discovery workflow, which also could be applied to discover active compounds for other targets quickly.Communicated by Ramaswamy H. Sarma.

Zinc ion thermal charging cell for low-grade heat conversion and energy storage.

Converting low-grade heat from environment into electricity shows great sustainability for mitigating the energy crisis and adjusting energy configurations. However, thermally rechargeable devices typically suffer from poor conversion efficiency when a semiconductor is employed. Breaking the convention of thermoelectric systems, we propose and demonstrate a new zinc ion thermal charging cell to generate electricity from low-grade heat via the thermo-extraction/insertion and thermodiffusion processes of insertion-type cathode (VO2-PC) and stripping/plating behaviour of Zn anode. Based on this strategy, an impressively high thermopower of ~12.5 mV K-1 and an excellent output power of 1.2 mW can be obtained. In addition, a high heat-to-current conversion efficiency of 0.95% (7.25% of Carnot efficiency) is achieved with a temperature difference of 45 K. This work, which demonstrates extraordinary energy conversion efficiency and adequate energy storage, will pave the way towards the construction of thermoelectric setups with attractive properties for high value-added utilization of low-grade heat.

Defect-rich and N-doped hard carbon as a sustainable anode for high-energy lithium-ion capacitors.

Lithium-ion capacitors (LICs) are regarded as the most potential devices in the energy storage systems. Unfortunately, the mismatched in the intrinsic kinetics and specific capacities between anode and cathode lead to a depressed electrochemical performance. Thus, designing an advanced electrode material that combines high performance with low-cost is one of the main challenges for LICs, especially in a sustainable anode material until now. Here, a high-energy LIC has been successfully developed using the defect-rich and N-doped hard carbon (DNC) as anode, which is prepared through the carbonization process of the low-cost biowaste sepia without additional template or catalyst. The DNC shows nanospherical structure with a diameter of about 100 nm. Owing to the two-pronged strategy of N-doping and defect engineering, it delivers a high specific capacity (580.3 mAh g-1 at 0.05 A g-1), excellent rate capability, and long cycle stability (1000 cycles). The electrochemical kinetic analysis and density functional theory (DFT) calculations have confirmed its prominent pseudocapacitive behaviors and excellent Li+ storage capability. As expected, the as-fabricated LIC delivers a remarkable energy density (101.7 Wh kg-1), an outstanding rate capability (56.3 Wh kg-1 at 12.5 kW kg-1), and a superior cycle lifespan (3000 cycles), demonstrating the tremendous potential for the next-generation energy storage systems.

Sodium-ion capacitors: Materials, Mechanism, and Challenges.

Sodium-ion capacitors (SICs), designed to attain high energy density, rapid energy delivery, and long lifespan, have attracted much attention because of their comparable performance to lithium-ion capacitors (LICs), alongside abundant sodium resources. Conventional SIC design is based on battery-like anodes and capacitive cathodes, in which the battery-like anode materials involve various reactions, such as insertion, alloying, and conversion reactions, and the capacitive cathode materials usually depend on activated carbon (AC). However, researchers have attempted to construct SICs based on battery-like cathodes and capacitive anodes or a combination of both in recent years. In this Minireview, charge storage mechanisms and material design strategies for SICs are summarized, with a focus on the battery-like anode materials from both inorganic and organic sources. Additionally, the challenges in the fabrication of SICs and future research directions are discussed.

[Dynamics of forage supplement and nutrition requirements of grazing sheep in alpine grasslands].

The dynamics of forage supply and nutrition requirements of sheep were monitored for a whole year under alpine grassland conditions in Sunan County, Gansu Province. The digestion and metabolism of grazed sheep were determined in different seasons. The results showed that the DE(9.76 MJ), CP(21.53%) and the ratio of crude protein to digestible energy (22.06 g.MJ-1) of forage were the highest in Spring, while the herbage dry matter yield and dry matter intake (60.51 +/- 3.42 g.W0.75kg-1.d-1) by grazed sheep were the lowest. Supplementary DM especially in energy should be provided. The ratio of crude protein to digestible energy was 17.62 g.MJ-1 in Summer, and was somewhat higher. The nitrogen utility of the forage would be improved, if energy feed was supplemented. Both the quality and quantity of forage produced in grasslands in Autumn could meet the sheep requirement. Whereas during Winter, neither forage yield nor nutritive value was sufficient for sheep, and the contents of the DE and CP of forage were the lowest in the year, which were 4.30 MJ and 4.63%, respectively. The nitrogen metabolism of sheep was negative. Therefore, DM, especially DE and CP, should be supplemented. To improve the conditions, it was necessary to develop seasonal animal husbandry, and combine the subsystems into coupling systems.