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.

Structure-Based Optimization of the Third Generation Type II Macrocycle TRK Inhibitors with Improved Activity against Solvent-Front, xDFG, and Gatekeeper Mutations.

The solvent-front (SF), gatekeeper, and xDFG motif mutations of tropomyosin receptor kinase (TRK) mediating acquired resistance of larotrectinib and entrectinib represent an unmet clinical need. To date, no effective drugs are being approved to overcome these mutants. Thus, a series of macrocycle compounds were designed and synthesized as new type II TRK inhibitors to combat clinically relevant mutations. The representative compound 10g exhibited excellent potency against wide type TRKA/C, TRKAG595R, TRKAG667C, and TRKAF589L with IC50 values of 5.21, 4.51, 6.77, 1.42, and 6.13 nM, respectively, and a good kinome selectivity against 378 kinases. 10g also strongly suppressed the proliferation of Ba/F3 cells transfected with SF, GK, xDFG, and others (Val to Met) single mutants with IC50 values of 1.43-47.56 nM. Moreover, 10g demonstrated ideal antitumor efficacy in both BaF3-CD74-NTRK1G595R and BaF3-CD74-NTRK1G667C xenograft models. The study provides a promising lead compound for pan-anticancer drug discovery.

M6ATMR: identifying N6-methyladenosine sites through RNA sequence similarity matrix reconstruction guided by Transformer.

Numerous studies have focused on the classification of N6-methyladenosine (m6A) modification sites in RNA sequences, treating it as a multi-feature extraction task. In these studies, the incorporation of physicochemical properties of nucleotides has been applied to enhance recognition efficacy. However, the introduction of excessive supplementary information may introduce noise to the RNA sequence features, and the utilization of sequence similarity information remains underexplored. In this research, we present a novel method for RNA m6A modification site recognition called M6ATMR. Our approach relies solely on sequence information, leveraging Transformer to guide the reconstruction of the sequence similarity matrix, thereby enhancing feature representation. Initially, M6ATMR encodes RNA sequences using 3-mers to generate the sequence similarity matrix. Meanwhile, Transformer is applied to extract sequence structure graphs for each RNA sequence. Subsequently, to capture low-dimensional representations of similarity matrices and structure graphs, we introduce a graph self-correlation convolution block. These representations are then fused and reconstructed through the local-global fusion block. Notably, we adopt iteratively updated sequence structure graphs to continuously optimize the similarity matrix, thereby constraining the end-to-end feature extraction process. Finally, we employ the random forest (RF) algorithm for identifying m6A modification sites based on the reconstructed features. Experimental results demonstrate that M6ATMR achieves promising performance by solely utilizing RNA sequences for m6A modification site identification. Our proposed method can be considered an effective complement to existing RNA m6A modification site recognition approaches.

Massive secretions in paragonimiasis pleural effusion: a new finding concerning clinical recognition and treatment.

Some paragonimiasis patients in Chongqing, southwest China, have recently exhibited pleural effusions (PEs) with massive viscous secretions. This study aimed to investigate their clinical characteristics, thereby promoting effective treatments. A 3-year retrospective review of paragonimiasis patients who were admitted for nonhomogeneous PEs at Chongqing University Three Gorges Hospital was conducted. Epidemiological data, symptoms, laboratory and imaging findings, treatments, and outcomes were analyzed. Twenty-eight patients were identified, of which 22 (78.6%) were males and 22 (78.6%) were rural residents. Respiratory (85.7%) and constitutional (57.1%) symptoms were common. Paragonimus-specific ELISA was positive in all patients. Eosinophilia was detected in all patients in peripheral blood and PEs. Irregular hyperdense signals were observed in PEs by chest CT scans (96.4%) and ultrasonography (100.0%). Thoracic closed drainage failed in 10 patients (conservative group) because of tube blockage and was eventually replaced by video-assisted thoracoscopic surgery (VATS). Eighteen patients (surgery group) initially underwent VATS, or thoracotomy surgery, without complications. Massive secretions, described as "bean-dregs" or "egg-floccule," were detected intraoperatively, which explained the imaging findings and tube blockage. All patients recovered well after 2-3 courses of postoperative praziquantel treatment. Viscous secretions in paragonimiasis patients warrant great concern. Irregular hyperdense signals in effusions are important characteristics in CT scans and ultrasonography. Treatments such as thoracic closed drainage may fail due to viscous secretions blocking the tube; therefore, surgeries should be considered. In-depth multidisciplinary research may help determine the optimal treatment strategy and reveal the origin of these secretions.

Switch type I to type II TRK inhibitors for combating clinical resistance induced by xDFG mutation for cancer therapy.

TRK xDFG mutation-induced acquired resistance of 1st generation inhibitors larotrectinib and entrectinib remains an unmet clinical need. Here we report a series of 6-(pyrrolidin-1-yl)imidazo[1,2-b]pyridazine-based derivatives as selective type II TRK inhibitors by hybridization. A representative compound 12d potently inhibited TRKA/B/C and TRKAG667C with IC50 values of 3.3, 6.4, 4.3 and 9.4 nM, respectively. 12d potently suppressed proliferation of a panel of Ba/F3 cells stably transformed with wild type, xDFG as well as solvent-front (SF) mutant TRK fusion proteins. Compared with larotrectinib and selitrectinib, 12d displayed superior inhibitory activity towards Ba/F3 cells harboring CD74-TRKAG667C and ETV6-TRKCG696C with IC50 values of 2.6 and 6.1 nM, respectively. Moreover, 12d also exhibited potent antiproliferation activity against Ba/F3-ETV6-TRKCG623R and Ba/F3-ETV6-TRKCG623E mutants with IC50 values of 31.0 and 28.2 nM, respectively. This work provided a new potential type II TRK inhibitor-based lead compound for the treatment of TRK driven cancers.

Targeting Gatekeeper Mutations for Kinase Drug Discovery.

Clinically acquired resistance is a major challenge in cancer therapies with small-molecule kinase inhibitors (SMKIs). Gatekeeper mutations in the ATP-binding pocket of kinases are the most common mutations leading to acquired resistance. To date, seven new-generation kinase inhibitors targeting gatekeeper mutations have been approved by the FDA; however, the clinical need is still unmet. Here, we systematically summarize the types of gatekeeper mutations across the kinase family, the structural basis for acquired resistance, and newly developed SMKIs targeting gatekeeper mutations as well as highlight the opportunities and challenges of kinase drug discovery for targeting gatekeeper mutations.

SAR1A regulates the RhoA/YAP and autophagy signaling pathways to influence osteosarcoma invasion and metastasis.

Osteosarcoma is the most prevalent form of primary bone malignancy affecting adolescents. Secretion-associated Ras-related GTPase 1A (SAR1A) is a key regulator of endoplasmic reticulum (ER) homeostasis, but its role as a regulator of osteosarcoma metastasis has yet to be clarified. Bioinformatics analyses revealed SAR1A and RHOA to be upregulated in osteosarcoma patients, with the upregulation of these genes being associated with poor 5-year metastasis-free survival rates. In addition, the upregulation of SAR1A and RHOA in osteosarcoma was highly positively correlated. Immunohistochemical analyses additionally revealed that SAR1A levels were increased in osteosarcoma pulmonary metastases. In vitro wound healing and Transwell assays indicated that knocking down SAR1A or RHOA impaired the invasive and migratory activity of osteosarcoma cells, whereas RHOA overexpression had the opposite effect. Western blotting and immunofluorescent staining revealed the inhibition of osteosarcoma cell epithelial-mesenchymal transition following SAR1A or RHOA knockdown; RHOA overexpression had the opposite effect. Following SAR1A knockdown, phalloidin staining indicated that osteosarcoma cells showed reduced lamellipodia formation. Endoplasmic reticulum stress levels and reactive oxygen species production were enhanced following the knockdown of SAR1A, as was autophagic activity, with lung metastases being reduced in vivo after such knockdown. Knocking down SAR1A suppresses osteosarcoma cell metastasis through the RhoA/YAP, ER stress, and autophagic pathways, offering new insights into the regulation of autophagic activity in the context of osteosarcoma cell metastasis and suggesting that these pathways could be amenable to therapeutic intervention.

A unique Co@CoO catalyst for hydrogenolysis of biomass-derived 5-hydroxymethylfurfural to 2,5-dimethylfuran.

The development of precious-metal-free catalysts to promote the sustainable production of fuels and chemicals from biomass remains an important and challenging target. Here, we report the efficient hydrogenolysis of biomass-derived 5-hydroxymethylfurfural to 2,5-dimethylfuran over a unique core-shell structured catalyst, Co@CoO that affords the highest productivity among all catalysts, including noble-metal-based catalysts, reported to date. Surprisingly, we find that the catalytically active sites reside on the shell of CoO with oxygen vacancies rather than the metallic Co. The combination of various spectroscopic experiments and computational modelling reveals that the CoO shell incorporating oxygen vacancies not only drives the heterolytic cleavage, but also the homolytic cleavage of H2 to yield more active Hδ- species, resulting in the exceptional catalytic activity. Co@CoO also exhibits excellent activity toward the direct hydrodeoxygenation of lignin model compounds. This study unlocks, for the first time, the potential of simple metal-oxide-based catalysts for the hydrodeoxygenation of renewable biomass to chemical feedstocks.

Discovery of the First Highly Selective and Broadly Effective Macrocycle-Based Type II TRK Inhibitors that Overcome Clinically Acquired Resistance.

Tropomyosin receptor kinase (TRK) secondary mutations mediating acquired resistance, especially at the solvent-front (SF) and the DFG motif, represent an unmet clinical need. Small-molecule macrocyclic kinase inhibitors have displayed significant advantages in overcoming clinical resistance driven by kinase mutations; however, all reported small-molecule macrocyclic TRK inhibitors are all type I inhibitors and are therefore much more sensitive to SF than xDFG mutations. Novel therapeutics for patients with xDFG resistance mutations are urgently needed. We report the first highly selective macrocycle-based potent type II TRK inhibitor, 7b, that exhibits high inhibitory potency toward various TRK fusion protein variants as well as wild type. 7b exhibited potent antiproliferative activity against Ba/F3 cells harboring CD74-TRKAG667C and ETV6-TRKCG696C with half-maximum inhibitory concentration (IC50) values of 6 and 1.7 nM, respectively. More importantly, 7b also showed potent antiproliferative activity against a panel of SF mutants (IC50 = 5.6-110 nM) and displayed extraordinary kinome selectivity.

Discovery of novel TrkA allosteric inhibitors: Structure-based virtual screening, biological evaluation and preliminary SAR studies.

Tropomyosin receptor kinases A (TrkA) is a potential therapeutic target for the treatment of numerous tumor types and chronic pain. However, most of the reported TrkA inhibitors are ATP competitive pan-Trks inhibitors that lack subtype selectivity. A selective TrkA inhibitor may provide valuable therapeutic benefits. Here, we described the discovery of novel TrkA allosteric inhibitors by structure-based virtual screening. A promising hit (D5261, TrkA cell IC50 = 3.32 µM) was selected for further studies. The binding free energy between TrkA and D5261 was calculated. In addition, the preliminary structure-activity relationship (SAR) studies with D5261 were investigated. The results suggest that D5261 can be used as a starting point for development of TrkA allosteric inhibitors.

Progress of Binder Structures in Silicon-Based Anodes for Advanced Lithium-Ion Batteries: A Mini Review.

Silicon (Si) has been counted as the most promising anode material for next-generation lithium-ion batteries, owing to its high theoretical specific capacity, safety, and high natural abundance. However, the commercial application of silicon anodes is hindered by its huge volume expansions, poor conductivity, and low coulombic efficiency. For the anode manufacture, binders play an important role of binding silicon materials, current collectors, and conductive agents, and the binder structure can significantly affect the mechanical durability, adhesion, ionic/electronic conductivities, and solid electrolyte interface (SEI) stability of the silicon anodes. Moreover, many cross-linked binders are effective in alleviating the volume expansions of silicon nanosized even microsized anodic materials along with maintaining the anode integrity and stable electrochemical performances. This mini review comprehensively summarizes various binders based on their structures, including the linear, branched, three-dimensional (3D) cross-linked, conductive polymer, and other hybrid binders. The mechanisms how various binder structures influence the performances of the silicon anodes, the limitations, and prospects of different hybrid binders are also discussed. This mini review can help in designing hybrid polymer binders and facilitating the practical application of silicon-based anodes with high electrochemical activity and long-term stability.

The Euscaphis japonica genome and the evolution of malvids.

Malvids is one of the largest clades of rosids, includes 58 families and exhibits remarkable morphological and ecological diversity. Here, we report a high-quality chromosome-level genome assembly for Euscaphis japonica, an early-diverging species within malvids. Genome-based phylogenetic analysis suggests that the unstable phylogenetic position of E. japonica may result from incomplete lineage sorting and hybridization event during the diversification of the ancestral population of malvids. Euscaphis japonica experienced two polyploidization events: the ancient whole genome triplication event shared with most eudicots (commonly known as the γ event) and a more recent whole genome duplication event, unique to E. japonica. By resequencing 101 samples from 11 populations, we speculate that the temperature has led to the differentiation of the evergreen and deciduous of E. japonica and the completely different population histories of these two groups. In total, 1012 candidate positively selected genes in the evergreen were detected, some of which are involved in flower and fruit development. We found that reddening and dehiscence of the E. japonica pericarp and long fruit-hanging time promoted the reproduction of E. japonica populations, and revealed the expression patterns of genes related to fruit reddening, dehiscence and abscission. The key genes involved in pentacyclic triterpene synthesis in E. japonica were identified, and different expression patterns of these genes may contribute to pentacyclic triterpene diversification. Our work sheds light on the evolution of E. japonica and malvids, particularly on the diversification of E. japonica and the genetic basis for their fruit dehiscence and abscission.

Genetic diversity and population structure of Euscaphis japonica, a monotypic species.

BACKGROUND: Understanding plant genetic diversity is important for effective conservation and utilization of genetic resources. Euscaphis japonica (Thunb.) Dippel, is a monotypic species with high phenotypic diversity, narrow distribution, and small population size. In this study, we estimated the genetic diversity and population structure of E. japonica using nine natural populations and inter-simple sequence repeat (ISSR) markers. Our results could provide a theoretical reference for future conservation and utilization of E. japonica. RESULTS: We obtained a total of 122 DNA bands, of which 121 (99.18%) were polymorphic. The average number of effective alleles (Ne = 1.4975), Nei's gene diversity index (H = 0.3016), and Shannon's information index (I = 0.4630) revealed that E. japonica possessed a high level of genetic diversity. We observed that E. japonica consisted of both deciduous and evergreen populations. UPGMA tree showed that the evergreen and deciduous E. japonica form a sister group. There is little genetic differentiation among geographic populations based on STRUCTURE analysis. The Dice's similarity coefficient between the deciduous and evergreen populations was low, and the Fst value was high, indicating that these two types of groups have high degree of differentiation. CONCLUSION: Rich genetic diversity has been found in E. japonica, deciduous E. japonica and evergreen E. japonica populations, and genetic variation mainly exists within the population. The low-frequency gene exchange between deciduous and evergreen populations may be the result of the differentiation of deciduous and evergreen populations. We suggest that in-situ protection, seed collection, and vegetative propagation could be the methods for maintenance and conservation of E. japonica populations.

TANK-binding kinase 1 (TBK1): An emerging therapeutic target for drug discovery.

Dysregulation of TANK-binding kinase 1 (TBK1) homeostasis leads to the occurrence and progression of many diseases, such as inflammation, autoimmune diseases, metabolic diseases, and cancer. Therefore, there is a need to develop TBK1 inhibitors as therapeutic agents. In this review, we highlight the diverse biological functions of TBK1 and summarize the promising small-molecule inhibitors of TBK1 that have the potential to be developed as therapeutic candidates.