Design, synthesis and biological evaluation of 5-amino-1H-pyrazole-4-carboxamide derivatives as pan-FGFR covalent inhibitors.

The aberrant activation of FGFRs plays a critical role in various cancers, leading to the development of several FGFR inhibitors in clinic. However, the emergence of drug resistance, primarily due to gatekeeper mutations in FGFRs, has limited their clinical efficacy. To address the unmet medical need, a series of 5-amino-1H-pyrazole-4-carboxamide derivatives were designed and synthesized as novel pan-FGFR covalent inhibitors targeting both wild-type and the gatekeeper mutants. The representative compound 10h demonstrated nanomolar activities against FGFR1, FGFR2, FGFR3 and FGFR2 V564F gatekeeper mutant in biochemical assays (IC50 = 46, 41, 99, and 62 nM). Moreover, 10h also strongly suppressed the proliferation of NCI-H520 lung cancer cells, SNU-16 and KATO III gastric cancer cells with IC50 values of 19, 59, and 73 nM, respectively. Further X-ray co-crystal structure revealed that 10h irreversibly binds to FGFR1. The study provides a new promising point for anticancer drug development medicated by FGFRs.

Research on fertilization decision method for rice tillering stage based on the coupling of UAV hyperspectral remote sensing and WOFOST.

Introduction: The use of chemical fertilizers in rice field management directly affects rice yield. Traditional rice cultivation often relies on the experience of farmers to develop fertilization plans, which cannot be adjusted according to the fertilizer requirements of rice. At present, agricultural drones are widely used for early monitoring of rice, but due to their lack of rationality, they cannot directly guide fertilization. How to accurately apply nitrogen fertilizer during the tillering stage to stabilize rice yield is an urgent problem to be solved in the current large-scale rice production process. Methods: WOFOST is a highly mechanistic crop growth model that can effectively simulate the effects of fertilization on rice growth and development. However, due to its lack of spatial heterogeneity, its ability to simulate crop growth at the field level is weak. This study is based on UAV remote sensing to obtain hyperspectral data of rice canopy and assimilation with the WOFOST crop growth model, to study the decision-making method of nitrogen fertilizer application during the rice tillering stage. Extracting hyperspectral features of rice canopy using Continuous Projection Algorithm and constructing a hyperspectral inversion model for rice biomass based on Extreme Learning Machine. By using two data assimilation methods, Ensemble Kalman Filter and Four-Dimensional Variational, the inverted biomass of the rice biomass hyperspectral inversion model and the localized WOFOST crop growth model were assimilated, and the simulation results of the WOFOST model were corrected. With the average yield as the goal, use the WOFOST model to formulate fertilization decisions and create a fertilization prescription map to achieve precise fertilization during the tillering stage of rice. Results: The research results indicate that the training set R2 and RMSE of the rice biomass hyperspectral inversion model are 0.953 and 0.076, respectively, while the testing set R2 and RMSE are 0.914 and 0.110, respectively. When obtaining the same yield, the fertilization strategy based on the ENKF assimilation method applied less fertilizer, reducing 5.9% compared to the standard fertilization scheme. Discussion: This study enhances the rationality of unmanned aerial vehicle remote sensing machines through data assimilation, providing a new theoretical basis for the decision-making of rice fertilization.

Exceeding Three-Electron Reactions in Polyanionic Cathode To Achieve High-Energy Density for Sodium-Ion Batteries.

Activating multielectron reactions of sodium superionic conductor (NASICON)-type cathodes toward higher energy density remains imperative to boost their application feasibility. However, multisodium storage with high stability is difficult to achieve due to the sluggish reaction kinetics, irreversible phase transitions, and negative structural degradation. Herein, a kind of NASICON-type Na2.5V1.5Ti0.5(PO4)3/C (NVTP-0.5) hierarchical microsphere consisting of abundant primary nanoparticles is designed, realizing a reversible 3.2-electron reaction with high stability. The optimized NVTP-0.5 cathode demonstrates an ultrahigh discharge capacity of 192.42 mAh g-1, energy density of up to 497.3 Wh kg-1 at 20 mA g-1, and capacity retention ratio of 94.1% after 1000 cycles at 1 A g-1. Additionally, the NVTP-0.5 cathode delivers excellent tolerance to extreme temperatures while also achieving a high-energy density of 400 Wh kg-1 (based on the cathode mass) in a full-cell configuration. Systematic in situ/ex situ analysis results confirm the multisodium storage processes of NVTP-0.5 involving successive redox reactions (V2+/V3+, Ti3+/Ti4+, and V3+/V4+ redox couples) and reversible structure evolution (solid-solution and biphasic mechanisms), which contribute to the high capacity and excellent cycling stability. This work indicates that the rational regulation of components with different functions can unlock more possibilities for the development of NASICON-type cathodes.

Selective type II TRK inhibitors overcome xDFG mutation mediated acquired resistance to the second-generation inhibitors selitrectinib and repotrectinib.

Neurotrophic receptor kinase (NTRK) fusions are actionable oncogenic drivers of multiple pediatric and adult solid tumors, and tropomyosin receptor kinase (TRK) has been considered as an attractive therapeutic target for "pan-cancer" harboring these fusions. Currently, two generations TRK inhibitors have been developed. The representative second-generation inhibitors selitrectinib and repotrectinib were designed to overcome clinic acquired resistance of the first-generation inhibitors larotrectinib or entrectinib resulted from solvent-front and gatekeeper on-target mutations. However, xDFG (TRKAG667C/A/S, homologous TRKCG696C/A/S) and some double mutations still confer resistance to selitrectinib and repotrectinib, and overcoming these resistances represents a major unmet clinical need. In this review, we summarize the acquired resistance mechanism of the first- and second-generation TRK inhibitors, and firstly put forward the emerging selective type II TRK inhibitors to overcome xDFG mutations mediated resistance. Additionally, we concluded our perspectives on new challenges and future directions in this field.

RPIOSL: construction of the radiation transfer model for rice leaves.

The radiative transfer model of vegetation leaves simulates the transmission mechanism of light inside the vegetation and simulates the reflectivity of blades according to the change law of different components in the process of plant growth. Based on the PIOSL model, this paper combines PIOSL with the structure of rice leaves to construct a radiation transfer model for rice leaves. The parameters of each layer of the RPIOSL model are determined by the Non-dominated Sorting Genetic Algorithm-III. (NSGA-III.) algorithm. The reflectance spectra of 218 rice leaf samples in different periods were simulated using the RPIOSL model. The results show that the mean (RMSE) between the simulated and measured spectra of the constructed RPIOSL model is 0.1074, which is 0.0191 lower than that of the PROSPECT model. Among them, the spectral simulation effect of RPIOSL model in yellow and red light band is the best, and the RMSE at tillering period, jointing period, heading period and grouting period are 0.0584, 0.0576, 0.0724 and 0.0820, respectively. Therefore, the establishment of the RPIOSL model can accurately describe the interaction mechanism between light, which is of great significance for the rapid acquisition of rice growth information and accurate crop management.