Design, synthesis, and biological evaluation of 2,4-diaminopyrimidine derivatives as potent Hematopoietic Progenitor Kinase 1 (HPK1) inhibitors.

HPK1 also referred to as MAP4K1, belongs to the category of mammalian STE20-like protein serine/threonine kinases. Its physiological function involves the down-regulation of T cell signals, and it is regarded as a new immune checkpoint of tumor immunology. In this study, we commenced our investigation with the hit compounds, focusing the efforts on structural optimization and SAR exploration to identify a novel class of 2,4-diaminopyrimidine HPK1 inhibitors. Notably, compound 14g exhibited a remarkable inhibitory effect on HPK1 kinase (IC50 = 0.15 nM), significantly suppressed the phosphorylation of the downstream adaptor protein SLP76 (pSLP76 IC50 = 27.92 nM), and effectively stimulated the secretion of the T cell activation marker IL-2 (EC50 = 46.64 nM). In vitro microsomal stability assay, compound 14g showed moderate stability in HLMs with T1/2 = 38.2 min and CLint = 36.4 µL·min-1·mg-1 proteins. In vivo pharmacokinetic studies, compound 14g demonstrated heightened plasma exposure (AUC0-inf = 644 ng·h·mL-1), extended half-life (T1/2 = 9.98 h), and reduced plasma clearance (CL = 52.3 mL·min-1·kg-1) compared to the reference compound after a single intravenous dose of 2 mg/kg in rats. These results indicated that compound 14g emerged as a promising inhibitor of HPK1.

Synthesis and biological evaluation of new series of benzamide derivatives containing urea moiety as sEH inhibitors.

The pharmacological inhibition of soluble epoxide hydrolase (sEH) was shown to reduce inflammation and pain. Herein, we described a series of newly synthesized sEH inhibitors with the trident-shaped skeleton. Intensive structural modifications led to the identification of compound B15 as a potent sEH inhibitor with an IC50 value of 0.03 ± 0.01 nM. Furthermore, compound B15 showed satisfactory metabolic stability in human liver microsomes with a half-time of 197 min. In carrageenan-induced inflammatory pain rat model, compound B15 exhibited a better therapeutic effect compared to t-AUCB and Celecoxib, which demonstrated the proof of potential as anti-inflammatory agents for pain relief.

Discovery of benzamide derivatives containing urea moiety as soluble epoxide hydrolase inhibitors.

The elevation of epoxy-fatty acids through inhibition of soluble epoxide hydrolase (sEH) is efficient for the treatment of inflammatory and pain-related diseases. Herein, we reported the discovery of a series of benzamide derivatives containing urea moiety as sEH inhibitors. Intensive structural modifications led to the identification of compound A34 as a potent sEH inhibitor with good physicochemical properties. Molecular docking revealed an additional hydrogen-bonding interaction between the unique amide scaffold and Phe497, contributing to sEH inhibition potency enhancement. Compound A34 exhibited outstanding inhibitory activity against human sEH, with an IC50 value of 0.04 ± 0.01 nM and a Ki value of 0.2 ± 0.1 nM. It also showed moderate systemic drug exposure and oral bioavailability in vivo metabolism studies. In carrageenan-induced inflammatory pain rat model, compound A34 exhibited a better therapeutic effect compared to t-AUCB and Celecoxib. Metabolism studies in vivo together with an inflammatory pain evaluation suggest that A34 may be a viable lead compound for the development of highly potent sEH inhibitors.

[Characteristics of anion and cation in rhizosphere soil of saline grassland in North China under different nitrogen addition levels]. / ä¸åŒæ°´å¹³æ°®æ·»åŠ ä¸‹åŽåŒ—ç›æ¸åŒ–è‰åœ°æ ¹é™ åœŸå£¤é˜´é˜³ç¦»å­ç‰¹å¾.

We investigated the effects and mechanisms of nitrogen additions (0, 1, 2, 4, 8, 16, 24, 32 g N·m-2·a-1) on contents of anion and cation in rhizosphere soil, bulk soil, and mixed rhizosphere and bulk soil in the heavily salinized grassland in the agro-pastoral ecotone of North China. The results showed that pH of rhizosphere, mixed and bulk soils decreased significantly with the increases of nitrogen addition levels. Moreover, pH of three soil types under the 32 g N·m-2·a-1 treatment decreased by 1.2, 0.9, and 0.6, respectively, while pH of rhizosphere soil decreased by 0.44 compared with the bulk soil. Na+ content of rhizosphere, mixed and bulk soils significantly decreased, while the NO3- content significantly increased. The proportion of Na+ content in total soluble salt content in rhizosphere soil decreased by 14% and that in bulk soil decreased by 12% after the 32 g N·m-2·a-1 addition. NO3- content increased by 29% in rhizosphere soil and by 26% in bulk soil. There was significant negative correlation between pH and NO3- content, and significant positive correlation between pH and Na+ content. The total soluble salt content of rhizosphere soil under the 32 g N·m-2·a-1 treatment was significantly reduced by 31.5%. Collectedly, nitrogen deposition could reduce soil pH and total soluble salt content of rhizosphere soil and alleviate saline-alkali stress.

Effects of Core Training on Sport-Specific Performance of Athletes: A Meta-Analysis of Randomized Controlled Trials.

Improving athletes' performance is a major topic of interest in studies on competitive sports. Core training has been used as a training method in daily life and rehabilitation, and recently, in competitive sports, with positive results. Previous experimental studies showed that core training can improve the fitness level of athletes (e.g., balance, core stability, etc.), but offer no consistent conclusions on whether it can improve sport-specific performance. The purpose of this study was to investigate the effect of core training on the sport-specific performance of athletes through a meta-analysis. Relevant studies on randomized controlled trials were selected, and we calculated the effect size using standardized mean difference values and the random effects model. Results showed that core training had almost no effect on athletes' power and speed, while agility showed a medium effect size but no statistical significance. On the other hand, there was a large effect on general athletic performance, such as core endurance and balance. Consequently, core training had a great effect on the core endurance and balance of athletes, but little effect on sport-specific performance. This result implies that more elaborate core training programs should be designed to improve the sport-specific performance of athletes.

Effects of nitrogen addition on rhizosphere soil properties in a salinized grassland.

We explored the impacts of nitrogen (N) inputs and the rhizosphere effect on the properties of rhizosphere and bulk soils in a salinized grassland in Northern Shanxi under N addition rates of 0, 1, 2, 4, 8, 16, 24 and 32 g N·m-2·a-1. The results showed that N addition significantly decreased soil pH, but significantly increased Ca2+, NO3--N and inorganic nitrogen contents in rhizosphere and bulk soil. With the increases of N addition rates, the contents of Ca2+, NO3--N, inorganic nitrogen in rhizosphere and bulk soils and total nitrogen in rhizosphere soil increased gradually, whereas the contents of Na+, K+, Mg2+, NH4+-N and amino acid in rhizosphere soil, and total nitrogen in bulk soil first increased and then decreased. Results of the principal component analysis showed that the responses of soil properties to low (≤8 g·m-2·a-1) and high nitrogen addition rates (>8 g·m-2·a-1) were significantly different. Compared with bulk soil, soil pH, the contents of organic acids and amino acids in rhizosphere soil were significantly lower by 0.71 units, 44.3% and 9.8%, respectively, while the contents of K+, Ca2+, Mg2+, NH4+-N, inorganic nitrogen, total carbon and total nitrogen in rhizosphere soil were significantly higher by 51.0%, 47.6%, 20.8%, 215.5%, 139.3%, 31.7% and 65.3%, respectively. These results indicated that rhizosphere effect on soil properties was stronger than that of nitrogen addition.

The complete chloroplast genome of Bothriochloa ischaemum.

Bothriochloa ischaemum (Linn.) 1936 is a high-quality perennial forage in Loess Plateau of China. In this study, we sequenced and characterized the complete chloroplast genome of B. ischaemum, which was a circular DNA of 138,316 bp in length, including a large single copy (LSC) region of 80,226 bp, a small single copy (SSC) region of 12,526 bp, and the circular DNA was separated by a pair of identical inverted repeat regions (IRs) of 22,782 bp each. A total of 134 genes were identified, including 87 protein-coding genes, 39 tRNA genes, and eight rRNA genes. Phylogenetic tree showed that B. ischaemum was closer to B. decipiens and B. alta, genus Bothriochloa was closely related to genus Pseudanthistiria. Our findings will be helpful for better understanding of genetic diversity of Bothriochloa plants.

Effects of feeding salt-tolerant forage cultivated in saline-alkaline land on rumen fermentation, feed digestibility and nitrogen balance in lamb.

BACKGROUND: Mixing salt-tolerant plants with other plants may affect rumen fermentation, which could result in an increase of feed conversion rate. The objective of this study was to evaluate the effects of partially or entirely replacing the corn stover with a mixture of salt-tolerant forage (Dahurian wildrye grass, weeping alkaligrass and erect milkvetch) in the diet of lambs on ruminal fermentation, feed digestibility and nitrogen (N) balance. Ratios of corn stover to the mixture of salt-tolerant forages in the four experimental diets were 100:0, 67:33, 33:67 and 0:100, respectively, for control, low (LF), medium (MF) and high (HF). RESULTS: Ruminal pH was lower (P = 0.048) with LF and MF than with control and HF diets. Total VFA concentration was consistently higher (P = 0.039) for LF and MF than for control and HF with increasing amount of salt-tolerant forage. Ratio of acetate to propionate was linearly (P = 0.019) decreased due to the decrease in acetate production. Digestibilities of OM, NDF and CP in the whole tract linearly (P < 0.002) decreased with increasing amount of salt-tolerant forage. Similarly, retained N and ratio of retained N to digestible N also linearly (P < 0.005) decreased. CONCLUSION: Feeding salt-tolerant forage cultivated in saline-alkaline land improved rumen fermentation with increased total VFA production, and changed the rumen fermentation pattern to increased butyrate production. However, the decreased feed digestibility in the whole digestive tract of lamb may reduce nutrient availability to animals and thus adversely affect animal productivity. Additionally, feeding salt-tolerant forages may require more protein supplement to meet animal requirements, because of the low protein content and low protein digestibility of the salt-tolerant forages.

Effects of precipitation change and nitrogen addition on soil net N mineralization in a saline-alkaline grassland of Northern Shanxi Province, China.

To explore the responses of soil net nitrogen (N) mineralization rate to precipitation varia-tion and nitrogen deposition in salinized grassland, we set precipitation manipulation and nitrogen addition experiments in the typical agro-pastoral ecotone saline-alkaline grassland of Northern Shanxi Province, China. The in situ soil net N mineralization rate was determined by top-cover buried PVC cylinder from May to September in 2019. The results showed that there were seasonal dynamics in soil net N mineralization rate. Soil net N mineralization rate was not affected by increase/decrease precipitation (±50%), nitrogen addition (10 g·m-2·a-1) or the combination of nitrogen addition and increase 50% precipitation treatments. The combination of nitrogen addition and 50% reduction of precipitation significantly improved soil net nitrification rate and net N mine-ralization rate by 10.8 and 8.6 times, respectively. Soil net nitrogen mineralization rate was positively related to soil water content, and negatively related to soil pH. The effects of nitrogen addition on soil nitrogen mineralization rate were dependent on precipitation conditions. Soil water content and pH were important factors regulating soil net nitrogen mineralization rate in the saline-alkaline grassland of Northern Shanxi Province. Therefore, to roundly assess the response model of soil N mine-ralization process to global change, it is necessary to consider the interaction of precipitation changes and nitrogen addition, and the soil physical and chemical properties of salinized grassland.

Short-term effects of grazing intensity on soil stoichiometric characteristics of typical grassland in the agro-pastoral ecotone of northern China.

Grazing is the dominant land use way for natural grasslands. Different grazing intensities could affect soil stoichiometry in grasslands by influencing the selective feeding by livestock, litter input, and microbial community structure. In this study, a grazing experiment was carried out in a grassland of agro-pastoral ecotone in Northern China for three years (2017-2019). The concentrations of total carbon (TC), total nitrogen (TN), dissolved organic carbon (DOC), dissolved nitrogen (DN), microbial biomass carbon (MBC), and microbial biomass nitrogen (MBN) in soils were measured. We analyzed the stoichiometric characteristics of those parameters. The results showed that different grazing intensities (1, 2, 4 sheep·0.2 hm-2) had no significant effect on soil TC after three years. The moderate grazing intensity significantly reduced soil TN in 10-20 cm layer in 2019. The light, moderate, and heavy grazing intensities significantly increased soil C/N at 10-20 cm layer, while grazing intensities did not affect soil DOC, DN and DOC/DN. The soil DOC and DN content showed a decreasing trend with the increase of grazing intensity in 2019. It indicated that continuous high intensity grazing might reduce soil dissolved nutrients. The light grazing inten-sity increased soil MBC, while heavy grazing intensity reduced soil MBC significantly, with the increase of grazing year. Different grazing intensities did not affect soil MBN and MBC/MBN.

The complete chloroplast genome of Medicago ruthenica cv. 'Taihang' (Fabaceae) from Shanxi, China.

Medicago ruthenica is an important perennial forage with multiple characteristics of resistance. In this study, we sequenced and characterized the complete chloroplast genome of M. ruthenica 'Taihang', which is 124, 254 bp in length. A total of 108 genes were identified, including 74 protein-coding, 30 tRNA, and four rRNA genes. Phylogenetic analysis based on 27 chloroplast genomes showed that M. ruthenica 'Taihang' has a close relationship with M. ruthenica from Qinghai Province, China. The data are useful in better understanding the genetic diversity and stress resistance of Medicago and contribute to the phylogenetic study of Trifolieae.

[Short-term Effects of Different Grazing Intensities on Greenhouse Gas Fluxes in Semi-arid Grassland].

Grazing is one of the most important ways for managing grassland in northern China. Different studies have focused on the effects of grazing on the structure and function of ecosystems. Grazing affects the structure and function of soil via biological and physical processes, such as animal trampling, feeding, and excretion, which further affects N2O emissions. However, there is less research on greenhouse gases (GHGs) emissions by grazing intensities in semi-arid grassland ecosystems in northern China. In this study, four different grazing intensities were considered in the semi-arid grassland ecosystem of the typical agro-pastoral ecotone in northern China (Youyu, Shanxi). The influence of different grazing intensities on GHG fluxes was studied by measuring GHGs fluxes in the growing season with an opaque static chamber. The results showed that ① Grazing had no effect on CO2 and N2O fluxes during the first year of grazing treatment. ② However, grazing decreased soil water content (P<0.05), moderate grazing intensity decreased microbial biomass carbon (P<0.05), and moderate and heavy grazing intensities reduced microbial biomass nitrogen (P<0.05). ③ Significant positive correlations between CO2 flux and soil temperature and soil moisture were observed. The correlation between temperature and CO2 emissions was increased by grazing. ④ There was a significant positive correlation between soil temperature, soluble nitrogen, soil microbial biomass nitrogen, CO2 flux, and N2O flux. Our results indicated that GHG, regulated by soil microorganisms, was affected by soil temperature and moisture.