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Plant growth promoting rhizobacteria (PGPR) offer an environmentally friendly and sustainable approach to combat pathogens and enhance crop production. The biocontrol activity of PGPR depends on their ability to colonize plant roots and synthesize antimicrobial compounds that inhibit pathogens. However, the regulatory mechanisms underlying these processes remain unclear. In this study, we isolated and characterized Bacillus velezensis 118, a soil isolate that exhibits potent biocontrol activity against Fusarium wilt of banana. Deletion of sigX, encoding an extracytoplasmic function (ECF) sigma factor previously implicated in controlling biofilm architecture in B. subtilis, reduced biocontrol efficacy. The B. velezensis 118 sigX mutant displayed reduced biofilm formation but had only a minor defect in swarming motility and a negligible impact on lipopeptide production. These findings highlight the importance of regulatory processes important for root colonization in the effectiveness of Bacillus spp. as biocontrol agents against phytopathogens. [ABSTRACT FROM AUTHOR] more...

Eothenomys miletus is an endemic species that inhabits the Hengduan Mountain regions (HDR) and serves as one of the primary hosts for plague and hantaviruses. While the physiological characteristics of E. miletus have been extensively studied, the molecular aspects, particularly the migration direction of E. miletus , remain unclear. In the present study, we utilized genomic data to investigate the migration direction of four populations: Ailaoshan (ALS), Jiangchuan (JC), Lijiang (LJ), and Deqin (DQ), which are distributed from south to north within the HDR. Our results indicated that the ALS population is positioned at the base of the phylogenetic tree, and admixture analysis revealed that the ALS population is more closely related to the JC and DQ populations. Integrate the molecular genetic structure, fossil records of E. miletus as well as the results of our research, we inferred that the migration direction of E. miletus may have been from south to north, suggesting that the DQ and JC populations may have originated from the migration of ALS. However, the migration patterns and origins of the LJ population require further investigation and discussion. Additionally, we focused on identifying genomic signatures of selection and local adaptation among the different populations. We identified three selected genes associated with the olfactory placode in DQ: Six1 , Six4 , and Sox2. We hypothesized that these genes may be linked to the DQ population's adaptation to the region's microclimate. In summary, the present study is the first to employ genomics to explore the migration direction of E. miletus , which is crucial for future research on the origins of Eothenomys. [ABSTRACT FROM AUTHOR] more...

Chemotherapy as a primary treatment for breast cancer is limited due to drug resistance in clinical treatment. The rapid proliferation and invasive biological properties of breast cancer, resulting in intratumoral hypoxia and adaptive antioxidation, are common manifestations of drug-resistant breast cancer. Photodynamic therapy is a potential strategy to overcome drug resistance, but its effectiveness is often limited by tumor hypoxia. In order to overcome the problem of tumor hypoxia and improve the effectiveness of photodynamic therapy, a strategy that employs ZIF-90 nanoparticles simultaneously delivering a hypoxia-induced drug (TPZ) and photosensitizer Ce6 labeled antisense nucleic acid (Ce6-G3139) into breast cancer cells was developed. Owing to the pH responsiveness of ZIF-90, TPZ and Ce6-G3139 are able to be efficiently released inside the tumor microenvironment. First, Ce6-G3139 can perform gene therapy, downregulating the expression of antiapoptotic protein BCL-2 and accelerating cell apoptosis. On the other hand, photosensitizer Ce6 can undergo photodynamic therapy (PDT), producing reactive oxygen species that interfere with the apoptosis mechanism of cells. More importantly, although the continuous consumption of oxygen in PDT aggravates the hypoxic environment of the tumor, the hypoxic-induced chemotherapy drug was further activated. Our research results indicate that the designed strategy targeting the hypoxic microenvironment of drug-resistant breast cancer exhibits significant anticancer effects both in vitro and in vivo, favoring the development of a PDT treatment paradigm that is effective against drug resistance under hypoxic conditions. [ABSTRACT FROM AUTHOR] more...

Numerous research studies have demonstrated the significant correlation of phosphatidylinositol‐3 kinase gamma (PI3Kγ) with the onset and progression of various human diseases, highlighting PI3Kγ as a promising therapeutic target. However, PI3Kγ demonstrates considerable similarity with other isoforms in the PI3K family, presenting significant challenges in the creation of PI3Kγ inhibitors. This study presents an ensemble‐based virtual screening approach to discover novel inhibitors targeting PI3Kγ. Eganelisib (IPI‐549) is the sole selective PI3Kγ inhibitor that has progressed to clinical trials, making it a significant model for the advancement of novel PI3Kγ inhibitors. Initially, common feature pharmacophore and receptor–ligand pharmacophore models were independently developed using IPI‐549 and its potent derivatives, in conjunction with the crystal complex of PI3Kγ/IPI‐549. Both qualitative pharmacophore models proved highly effective at distinguishing between active and inactive compounds. Then, four widely utilized docking programs were chosen for assessment, where the Glide_SP mode demonstrated superior predictive accuracy in sampling ligand conformations during binding, effectively distinguishing between PI3Kγ inhibitors and noninhibitors. Finally, a virtual screening protocol was conducted to screen the ChEMBL database, utilizing similarity search, consensus‐based pharmacophore mapping, and sequential molecular docking. This process resulted in the identification of multiple molecules exhibiting notable promise as potent PI3Kγ inhibitors. [ABSTRACT FROM AUTHOR] more...

Photothermal therapy (PTT), as a tumor optical treatment strategy, has the characteristics of being minimally invasive, precise and safe in the treatment of tumors. However, the efficacy of photothermal treatment is usually affected by the photothermal conversion efficiency of the material and the expression of heat shock protein in tumor cells. Ti3C2, a kind of MXene, is a novel two-dimensional material with excellent photothermal conversion efficiency and multiple unique characteristics, making it a promising candidate for multimodal tumor therapy. Therefore, inhibiting the synthesis of heat shock protein 90 (HSP90) in the process of photothermal therapy can reduce the heat resistance of tumor cells, thereby improving the effect of photothermal therapy. In this study, we highlight the potential of utilizing hyaluronic acid (HA) modified Ti3C2 (Ti3C2@HA) as a carrier for delivering anti-sense oligonucleotides of HSP90 to inhibit HSP90 expression and enhance PPT efficacy. Under laser irradiation, the designed MXene-based nanocomposite (Ti3C2@ASO@HA) significantly inhibited the growth and effectively suppressed the migration of tumor cells. In addition, decreased expression of HSP90 is confirmed by western blotting. The results of this investigation provide a promising strategy for enhancing the photothermal therapy effects of tumor. [ABSTRACT FROM AUTHOR] more...

Rice sheath blight is a serious disease caused by Rhizoctonia solani that reduces rice yield. Currently, there is a lack of efficient and environmentally friendly control methods. In this study, we found that Bacillus velezensis (B. velezensis) Y6 could significantly inhibit the growth of mycelium in Rhizoctonia solani, and its control efficiency against rice sheath blight was 58.67% (p < 0.01) in a pot experiment. Lipopeptides play an important role in the control of rice sheath blight by B. velezensis Y6, among which iturin and fengycin are essential, and iturin W, a novel lipopeptide in B. velezensis, plays a major role in lipopeptide antagonism to Rhizoctonia solani. In the field, we also found that inoculation with B. velezensis Y6 can increase rice yield (dry weight) by 11.75%. Furthermore, the transcriptome profiling results of the rice roots revealed that there were a total of 1227 differential genes (DEGs) regulated when treated with Y6, of which 468 genes were up-regulated and 971 genes were down-regulated in rice roots compared with the control. Among them, the DEGs were mainly distributed in biological processes (BP) and were mainly enriched in response to stimulus (GO:0050896), response to stress (GO:0006950), and response to abiotic stimulus (GO:0009628). According to the KEGG pathway analysis, there were 338 DEGs classified into 87 KEGG functional pathway categories. Compared with the control, a large number of enriched genes were distributed in phenylpropanoid biosynthesis (map00940), glutathione metabolism (map00480), glycolysis/gluconeogenesis (map00010), and amino sugar and nucleotide sugar metabolism (map00520). In summary, this investigation provides a new perspective for studying the molecular mechanism of B. velezensis in controlling rice sheath blight. [ABSTRACT FROM AUTHOR] more...

Indole-3-acetic acid (IAA), as an important regulator of potato growth, seriously affects the growth and yield of potato. Although many studies have reported that IAA-producing Bacillus can promote plant growth, little research has been conducted on its synthesis pathway and molecular mechanisms. In this study, an IAA-producing strain WL35 was identified as Fitibacillus barbaricus, and its yield was 48.79 mg·L−1. The results of the pot experiments showed that WL35 significantly increased plant height, stem thickness, chlorophyll content, and number of leaves of potato plants by 31.68%, 30.03%, 32.93%, and 36.59%, respectively. In addition, in the field experiments, WL35-treated plants increased commercial potato yield by 16.45%, vitamin C content by 16.35%, protein content by 75%, starch content by 6.60%, and the nitrogen, phosphorus, and potassium accumulation by 9.98%, 12.70%, and 26.76%, respectively. Meanwhile, the synthetic pathway of WL35 was found to be dominated by the tryptophan-dependent pathway, the IAM, TAM, and IPA pathways worked together, and the pathways that played a role at different times were different. Furthermore, RNA-seq analysis showed that there were a total of 2875 DEGs regulated in the samples treated with WL35 seed dressing compared with the CK, of which 1458 genes were up-regulated and 1417 genes were down-regulated. Potato roots express differential genes enriched in processes such as carbohydrate metabolism processes and cellular polysaccharide metabolism, which regulate potato plant growth and development. The above results provide a theoretical basis for the further exploration of the synthesis pathway of IAA and its growth-promoting mechanism in potato. [ABSTRACT FROM AUTHOR] more...

Triple negative breast cancer (TNBC) represents a highly aggressive variant of breast cancer characterized by elevated rates of recurrence and mortality. Chemotherapy's application as a main cancer therapy is restricted due to its harmful side effects and resistance to medication. In this study, we utilized a covalent organic framework (COF) to apply indocyanine green (ICG), a photothermal agent, and gambogic acid (GA), an inhibitor of heat shock protein 90 (HSP90), to treat triple negative breast cancer. MTT results showed that the viability of tumor cells decreased more under laser irradiation conditions after the addition of GA than in the COF@ICG group. In addition, protein blotting results showed that under the action of GA, the blank group exhibited significantly higher HSP90 expression levels than the experimental group. The above results indicate that COF@ICG@GA enhances the therapeutic effect of PTT on cancer by inhibiting the expression of HSP90 in triple negative breast cancer cells and enhancing the sensitivity of tumor cells to temperature. [ABSTRACT FROM AUTHOR] more...

The phosphatidylinositol‐3 kinase (PI3K) pathway is a crucial intracellular signaling pathway within living cells. The hyperactivation of PI3K signaling cascades is a common occurrence in human cancers, rendering PI3K a promising therapeutic target. Although several PI3K inhibitors are already available on the market, the adverse side effects of current therapies continue to highlight the necessity for the development of novel PI3K inhibitors. In this study, a virtual screening strategy employing naïve Bayesian classification (NBC) models, based on multicomplex‐based molecular docking and pharmacophore modeling, is developed. First, the docking accuracy and scoring reliability of four docking software are assessed, and Glide demonstrated higher predictability for PI3K inhibitors. Second, pharmacophore models are generated based on the current reported PI3K‐inhibitor interactions, and five pharmacophore hypotheses displayed significant capability in discriminating active PI3K molecules from inactive ones. Subsequently, three NBC models are constructed based on molecular docking and/or pharmacophore models, and the validation results showed that the NBC model, combining multicomplex‐based molecular docking and pharmacophore, significantly improved the hit rate of virtual screening against PI3K. Finally, the optimal NBC model is employed for virtual screening against the ChEMBL database, leading to the identification of multiple molecules with high potential as active PI3K inhibitors. [ABSTRACT FROM AUTHOR] more...

Amino acid transporters with different categories are highly expressed in intestinal epithelial cells for maintaining the essential metabolism of body. The zwitterionic property of amino acid with α‐amino and α‐carboxyl also has tremendous potential to conquer the mucus barrier. Therefore, Glu‐derived amphiphilic block polymers [i. e. poly(lactic acid)‐b‐poly(glutamine)25 (PPQ) and poly(lactic acid)‐b‐poly(glutamate)25 (PPD)] were rational designed and Glu‐derived zwitterionic micelles (PPQ‐M and PPD‐M) were further prepared toward oral delivery. In comparison with PEGylated micelles (PEG‐M), PPD‐M and PPQ‐M possessed superior mucus permeability. In addition, enhanced cellular internalization capacity was also detected in both zwitterionic micelles, which was mainly mediated by multiple amino acid transporters. The cellular uptake efficiency of PPQ‐M was obviously higher than that of PPD‐M due to the glutamine constitutional unit of PPQ‐M with higher affinity to amino acid transporters. Furthermore, the retrograde pathway played an important role in the intracellular transport (including transcytosis) of both zwitterionic micelles. Excellent villi absorption of zwitterionic micelles was observed in situ, which gave a convincing evidence for oral delivery application prospect. The results of this research demonstrated that Glu‐derived zwitterionic micelles with distinguished capacity of conquering intestinal mucosal barrier, have promising potential toward oral delivery. [ABSTRACT FROM AUTHOR] more...

An important objective of evolutionary biology has always been to grasp the evolutionary and genetic processes that contribute to speciation. The present work provides the first detailed account of the genetic and physiological adaptation to changing environmental temperatures as well as the reasons causing intraspecific divergence in the Eothenomys miletus from the Hengduan Mountain (HM) region, one of the biodiversity hotspots. One hundred sixty‐one E. miletus individuals from five populations in the HM region had their reduced‐representation genome sequenced, and one additional individual from each community had their genomes resequenced. We then characterized the genetic diversity and population structure of each population and compared the phenotypic divergence in traits using neutral molecular markers. We detected significant phenotypic and genetic alterations in E. miletus from the HM region that were related to naturally occurring diverse habitats by combining morphometrics and genomic techniques. There was asymmetric gene flow among the E. miletus populations, indicating that five E. miletus populations exhibit an isolation‐by‐island model, and this was supported by the correlation between FST and geographic distance. Finally, PST estimated by phenotypic measures of most wild traits were higher than differentiation at neutral molecular markers, indicating directional natural selection favoring different phenotypes in different populations must have been involved to achieve this much differentiation. Our findings give information on the demographic history of E. miletus, new insights into their evolution and adaptability, and literature for studies of a similar nature on other wild small mammals from the HM region. [ABSTRACT FROM AUTHOR] more...

Extensive research has accumulated suggesting that Janus kinase 3 (JAK3) is closely related to the occurrence and development of various human diseases, making JAK3 a highly potential drug target. However, JAK3 has high homology with other members of the JAK family, making the development of JAK3 inhibitors full of challenges. Thus, here, a naïve Bayesian classification (NBC) model based on multiple JAK3 protein conformations, which integrates molecular docking, pharmacophore, and molecular descriptors, is developed to find novel JAK3 inhibitors. First, the validation set is used to prove whether molecular docking or pharmacophore, integrating multiple JAK3 conformations always has higher prediction accuracy than that of any single conformation. Second, external prediction reveals that the NBC model combining molecular docking, pharmacophore, and important molecular features could significantly improve the enrichment of active JAK3 inhibitors. Finally, the optimal NBC model is utilized for virtual screening against a large chemical database and some compounds with high Bayesian scores are identified. Altogether, the machine learning‐based virtual screening protocol not only has strong efficiency but also has high screening accuracy. It is hoped that the developed virtual screening strategy could provide valuable guidance for the discovery of novel JAK3 inhibitors. [ABSTRACT FROM AUTHOR] more...