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F. taipaiensis P. Y. Li represents a significant asset within traditional Chinese medicinal flora, though it confronts the challenge of germplasm deterioration during its cultivation phase. This study aimed to discern the implications of single strains or combinations of diverse growth-promoting actinomycetes on the growth metrics, antioxidant competence and pertinent gene expression in the leaves of F. taipaiensis. The result revealed that the malondialdehyde content within the plant's leaves notably diminished in the treatment groups compared to the CK group, with the S6 group showcasing the most pronounced malondialdehyde reduction, amounting to approximately one-third of the CK's value. Leaf area, length and width peaked in the S5 cohort, registering values 4.55, 2.46 and 1.85 times surpassing the CK group. Concurrently, plant height and stem thickness were maximal in the S6 group, being 2.29 and 1.75 times that of the CK group, whereas leaf thickness reached its zenith in the S7 group, marking a 2.17-fold elevation compared to the CK. Photosynthetic pigments, soluble sugars and soluble proteins in the leaves, exhibited augmentation across the inoculated groups to varying magnitudes. Specifically, the S5 group was superior in photosynthetic metrics and pigments, while the S6 group manifested the highest soluble sugar concentration, which was 1.35 times that of the CK. The S3 group demonstrated the pinnacle of soluble protein content, an impressive 5.86-fold increment relative to the CK group. The enzymatic activities of superoxide dismutase, peroxidase and catalase, along with their affiliated gene expressions, were observably augmented in the inoculated groups, with the S5 group standing out. To encapsulate, the actinomycete inoculation holds potential in fostering the growth and maturation of F. taipaiensis, amplifying its environmental resilience. The revelations from this study extend valuable insights for the judicious choice of microbial fertilizers in the cultivated propagation of Fritillaria taipaiensis P. Y. Li.

Abstract Janus kinase 2 (JAK2) has been regarded as an essential target for the treatment of myeloproliferative neoplasms (MPNs). BBT594 and CHZ868, Type-II inhibitors of JAK2, illustrate satisfactory efficacy in preclinical MPNs and acute lymphoblastic leukemia (ALL) models. However, the L884P mutation of JAK2 abrogates the suppressive effects of BBT594 and CHZ868. In this study, conventional molecular dynamics (MD) simulations, umbrella sampling (US) simulations and MM/GBSA free energy calculations were employed to explore how the L884P mutation affects the binding of BBT594 and CHZ868 to JAK2 and uncover the resistance mechanism induced by the L884P mutation. The results provided by the US and MD simulations illustrate that the L884P mutation enhances the flexibility of the allosteric pocket and alters their conformations, which amplify the conformational entropy change (−TΔS) and weaken the interactions between the inhibitors and target. Additionally, the structural analyses of BBT594 and CHZ868 in complex with the WT JAK2 illustrate that the drug tail with strong electronegativity and small size located in the allosteric pocket of JAK2 may enhance anti-resistance capability. In summary, our results highlight that both of the changes of the conformational entropies and enthalpies contribute to the L884P-induced resistance in the binding of two Type-II inhibitors into JAK2 kinase.

This study aimed to examine the effects of inoculating Fritillaria taipaiensis P.Y.Li leaves with different strains of potassium-solubilizing bacteria (KSB), or combinations thereof, focusing on aspects of photosynthesis and physiological and biochemical characteristics. At present, some studies have only studied the rhizosphere microbial community characteristics of F. taipaiensis and have not discussed the effects of different microbial species on the growth promotion of F. taipaiensis. This paper will start from the perspective of potassium-solubilizing bacteria to conduct an in-depth study. Seed cultivation commenced at the base with three different KSBs in early October 2022. The growth of F. taipaiensis leaves was observed after different treatments. Both single-plant and compound inoculations were executed. A total of eight treatment groups were established, with aseptic fertilizer and sterilized soil functioning as the control group. The results reveal that intercellular CO2 concentration (Ci), stomatal conductance (Gs), and transpiration rate (Tr) were at their apex in the S7 group. Most treatment groups exhibited an increase in leaf area, photosynthetic pigment content, soluble sugar, soluble protein, Superoxide Dismutase (SOD), Peroxidase (POD), Catalase (CAT) activities, and proline content. The expression levels of POD, SOD, and CAT genes were evaluated, following inoculation with different KSB. The highest was the S7 group. The inoculation with various KSB, or combinations thereof, appears to bolster the growth and development of F. taipaiensis. The composite inoculation group S7, comprising Bacillus cereus, Burkholderia cepacia, and Bacillus subtilis, manifested the most favorable impact on the diverse indices of F. taipaiensis, thereby furnishing valuable insights for the selection of bacterial fertilizer in the artificial cultivation of F. taipaiensis. [ABSTRACT FROM AUTHOR]

Fritillaria taipaiensis P. Y. Li is a widely used medicinal herb in treating pulmonary diseases. In recent years, its wild resources have become scarce, and the demand for efficient artificial cultivation has significantly increased. This article is the first to apply phosphate solubilizing bacteria isolated from the rhizosphere soil of F. taipaiensis P. Y. Li to the cultivation process of F. taipaiensis P. Y. Li. The aim is to identify suitable reference strains for the artificial cultivation and industrial development of F. taipaiensis P. Y. Li by examining the effects of various phosphate solubilizing bacteria and their combinations on photosynthesis, physiological and biochemical properties, and gene expression related to the protective enzyme system in F. taipaiensis P. Y. Li. The experiment, conducted in pots at room temperature, included a control group (CK) and groups inoculated with inorganic phosphorussolubilizing bacteria: W1 (Bacillus cereus), W2 (Serratia plymuthica), W12 (Bacillus cereus and Serratia plymuthica), and groups inoculated with organophosphorus-solubilizing bacteria: Y1 (Bacillus cereus), Y2 (Bacillus cereus), Y12 (Bacillus cereus and Bacillus cereus), totaling seven groups. Compared to CK, most growth indices in the bacterial addition groups showed significant differences, with W12 achieving the highest values in all indices except the leaf area index. The content of photosynthetic pigments, photosynthetic parameters, and osmoregulatory substances increased variably in each bacterial treatment group. W12 exhibited the highest content of chlorophyll a and soluble protein, while W1 had the highest free proline content. The activities of peroxidase (POD), superoxide dismutase (SOD), and catalase (CAT) in all inoculated groups were higher than in CK, with significant changes in SOD and CAT activities. The malondialdehyde (MDA) content in all inoculated groups was lower than in CK, with Y12 being the lowest, at approximately 30% of CK. Gene expression corresponding to these three enzymes also increased variably, with POD expression in Y2 being the highest at 2.73 times that of CK. SOD and CAT expression in Y12 were the highest, at 1.84 and 4.39 times that of CK, respectively. These results indicate that inoculating phosphate solubilizing bacteria can enhance the growth of F. taipaiensis P. Y. Li, with the mixed inoculation groups W12 and Y12 demonstrating superior effects. This lays a theoretical foundation for selecting bacterial fertilizers in the cultivation process of F. taipaiensis P. Y. Li. [ABSTRACT FROM AUTHOR]

Exposure to organophosphorus compounds (OPs) may be fatal if untreated, and a clear and present danger posed by nerve agent OPs has become palpable in recent years. OPs inactivate acetylcholinesterase (AChE) by covalently modifying its catalytic serine. Inhibited AChE cannot hydrolyze the neurotransmitter acetylcholine leading to its build-up at the cholinergic synapses and creating an acute cholinergic crisis. Current antidotes, including oxime reactivators that attack the OP-AChE conjugate to free the active enzyme, are inefficient. Better reactivators are sought, but their design is hampered by a conformationally rigid portrait of AChE extracted exclusively from 100K X-ray crystallography and scarcity of structural knowledge on human AChE (hAChE). Here, we present room temperature X-ray structures of native and VX-phosphonylated hAChE with an imidazole-based oxime reactivator, RS-170B. We discovered that inhibition with VX triggers substantial conformational changes in bound RS-170B from a "nonproductive" pose (the reactive aldoxime group points away from the VX-bound serine) in the reactivator-only complex to a "semi-productive" orientation in the VX-modified complex. This observation, supported by concurrent molecular simulations, suggested that the narrow active-site gorge of hAChE may be significantly more dynamic than previously thought, allowing RS-170B to reorient inside the gorge. Furthermore, we found that small molecules can bind in the choline-binding site hindering approach to the phosphorous of VX-bound serine. Our results provide structural and mechanistic perspectives on the reactivation of OP-inhibited hAChE and demonstrate that structural studies at physiologically relevant temperatures can deliver previously overlooked insights applicable for designing next-generation antidotes. [ABSTRACT FROM AUTHOR]