Fosmidomycin (FOS) is a naturally occurring compound active against the enzyme DXR in the MEP pathway, and using it as a template for lead structure design is an effective strategy in developing new active compounds. In this work, by replacing the hydroxamate unit of FOS with pyrazole, isoxazole and the related heterocycles that also have the metal ion binding affinity, while retaining the monophosphonic acid in FOS or replacing it with a bisphosphonic acid group, heterocycle-containing mono- and bisphosphonic acid compounds as FOS analogs were designed. The key steps involved in the facile synthesis of these FOS analogs include the Michael addition of diethyl vinylphosphonate or tetraethyl vinylidenebisphosphonate to β-dicarbonyl compounds and the subsequent cyclic condensation with hydrazine or hydroxylamine. Two additional isoxazolinone-bearing FOS analogs were synthesized by the Michaelis-Becker reaction with diethyl phosphite as a key step. The bioactivity evaluation on model plants demonstrated that several compounds have better herbicidal activities compared to FOS, with the most active compound showing a 3.7-fold inhibitory activity on Arabidopsis thaliana, while on the root and stalk of Brassica napus L. and Echinochloa crus-galli in pre-emergence inhibitory activity test, the activities of this compound were found to be 3.2- and 14.3-, 5.4- and 9.4-fold, respectively, and in post-emergency activity test on Amaranthus retroflexus and Echinochloa crus-galli, 2.2- and 2.0-fold inhibition activities were displayed. Despite the significant herbicidal activity, this compound exhibited a DXR inhibitory activity lower than that of FOS but comparable to that of other non-hydroxamate DXR inhibitors, and the dimethylallyl pyrophosphate rescue assay gave no statistical significance, suggesting a different target might be involved in the inhibiting process. This work demonstrates that using bioisosteric replacement can be considered a valuable strategy for discovering new FOS analogs that may have high herbicidal activity.

Coal mining has caused a significant loss of nitrogen content of soil in mining areas. This article studies the effects of organic fertilizer, inorganic fertilizer, and combined application of Pseudomonas fluorescens with the ability of nitrogen fixation on soil nitrogen accumulation and composition in the reclamation area of Tunlan Coal Mine from 2016 to 2022 under the condition of equal nitrogen application, providing scientific basis for microbial fertilization and rapid increase of nitrogen content in the reclaimed soil of mining areas. The results showed that as the reclamation time increased, the nitrogen content and its composition structure of the soil treated with fertilization rapidly evolved towards normal farmland soil. The soil nitrogen content increased the fastest in the treatment of Pseudomonas fluorescens + organic fertilizer (MB), compared with inorganic fertilizer (CF), organic fertilizer (M), and Pseudomonas fluorescens + inorganic fertilizer (CFB) treatments, the treatment of Pseudomonas fluorescens + organic fertilizer (MB) can bring the total nitrogen (TN) content of the soil to normal farmland soil levels 1-3 years earlier. The comprehensive scores of Pseudomonas fluorescens + organic fertilizer (MB) and Pseudomonas fluorescens + inorganic fertilizer (CFB) on the two principal components were increased 1.58 and 0.79 than those of organic fertilizer (M) and inorganic fertilizer (CF) treatments, respectively. This further indicates that the combination of Pseudomonas fluorescens and organic fertilizer has a better effect on improving soil nitrogen accumulation than the combination of Pseudomonas fluorescens and inorganic fertilizer. At the same time, the application of Pseudomonas fluorescens will increase the content of unknown nitrogen (UN) in acid-hydrolysable nitrogen (AHN), and decrease the content of amino acid nitrogen (AAN) and ammonia nitrogen (AN), relatively. However, there was no significant effect on the content of ammonium nitrogen (NH4+-N) and nitrate nitrogen (NO3--N) in soil inorganic nitrogen (SMN). When combined with inorganic fertilizer, the contribution of soil mineralized nitrogen (SMN) to total nitrogen (TN) increased by 14.78%, while when combined with organic fertilizer, the contribution of acid-hydrolysable nitrogen (AHN) to total nitrogen (TN) increased by 44.77%. In summary, the use of Pseudomonas fluorescens is beneficial for nitrogen recovery in the reclaimed soil of coal mining areas. The optimal fertilization method under the experimental conditions is the combination of Pseudomonas fluorescens and organic fertilizer.

The use of ARPIs has led to an increase in the proportion of AR-null prostate cancer, including NEPC and DNPC, but the mechanism underlying this lineage transition has not been elucidated. We found that ID2 expression was increased in AR-null prostate cancer. In vitro and in vivo studies confirmed that ID2 promotes PCa malignancy and can confer resistance to enzalutamide in PCa cells. We generated a ID2 UP50 signature, which is capable to determine resistance to enzalutamide and also valuable for predicting patient prognosis. Functional experiments showed that ID2 could activate the stemness-associated JAK/STAT and FGFR signaling while inhibiting the AR signaling pathway. Our study indicates that ID2 promotes the acquisition of a stem-like phenotype in adenocarcinoma cells, leading to resistance to ADT and next-generation ARPIs in prostate cancer.