Rhoptry protein 18 (ROP18) is a key virulence factor of Toxoplasma gondii. The host's immune responses mediated by immune-related GTPases (IRGs) could be blocked by ROP18's kinase activity. ROP18 ...also interacts with various substrates, such as activating transcription factor 6 beta (ATF6β) and affects multiple physiological functions within host cells, thereby inducing intense virulence. In this study, competitive inhibitors targeted to ROP18 were subjected to virtual screening based on the principle of structure-based drug design (SBDD).
The preparation of the ROP18 structure was conducted using the "Structure Prepare" function of Molecular Operating Environment (MOE) software. The ATP-binding pocket was selected as the starting point for virtual screening. Construction of the pharmacophore model used Extended Hückel Theory (EHT) half-quantitative measurement and construction, as well as the characteristics of Type I kinase inhibitors. The pharmacophore model of ROP18 was imported into the Specs database for small molecule similarity screening using EHT pharmacophore measurement. Hit compounds were selected using the functions of London dG and generalized-born volume integral/weighted surface area (GBVI/WSA) scoring. The top 100 hits were analyzed by molecular docking and structure activity relationships (SAR) analysis.
The final pharmacophore comprised three typical characteristics: three hydrogen bond acceptors/donors, two ring aromatic features occupying the hydrophobic core, and one cation group feature targeted to the terminus of ATP. A total of 1314 hit compounds analogous to ROP18 pharmacophore were passed through the Specs. After two rounds of docking, 25 out of 100 hits were identified as belonging to two main scaffold types: phthalimide ring structure, thiazole ring and styrene structure. Additionally, the screen also identified 13 inhibitors with distinct scaffold types. The docking models and SAR analysis demonstrated that these hits could engage in multiple hydrogen bonds, salt bridges halogen bonds, and hydrophobic interactions with ROP18, and para-position halo substituents on the benzene ring may enhance their affinity scoring.
A pharmacophore against the ROP18 ATP-binding pocket was successfully constructed, and 25 representative inhibitors from 15 scaffold clusters were screened using the Specs database. Our results provide useful scaffold types for the chemical inhibition of ROP18 or alternative conformations to develop new anti-toxoplasmosis drug leads.
Feed efficiency (FE) is one of the most important economic traits in the porcine industry. In this study, high-throughput RNA sequencing (RNA-seq) was first utilized for brain tissue transcriptome ...analysis in pigs to indicate the potential genes and biological pathways related to FE in pigs. A total of 8 pigs with either extremely high-FE group (HE-group) or low-FE group (LE-group) were selected from 225 Duroc × (Landrace × Yorkshire) (DLY) pigs for transcriptomic analysis. RNA-seq analysis was performed to determine differentially expressed genes (DEGs) between the HE- and LE-group, and 430 DEGs were identified in brain tissues of pigs (|log
(FoldChange)| > 1; adjusted
-values <0.05). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that the DEGs were mainly enriched in synaptic signaling or transmission, and hormone secretion pathways, in which insulin secretion, and oxytocin signaling pathways were closely associated with FE by regulating feeding behavior and energy metabolism (adjusted
-values <0.05). Further, the transcription factors (TFs) analysis and gene co-expression network analysis indicated three hub differentially expressed TFs (
,
, and
) that affected FE by mainly regulating feeding behavior, insulin sensitivity, or energy metabolism. Our findings suggest several potential TFs and biological pathways for further investigations of FE in pigs.
A highly regioselective method for the palladium-catalyzed direct cross-coupling of imidazo1,2-apyridines with arylboronic acids has been developed by using O2 as oxidant. This process can be applied ...to a wide range of imidazo1,2-apyridines and arylboronic acids with excellent C-3-regioselectivity. It provides a new way for developing CC bond-forming processes of multisubstituted imidazo1,2-apyridines, which are common structural motifs in natural products and pharmaceuticals.
•Pd-catalyzed cross-coupling of imidazo1,2-apyridines with aryl boronic acids•It represents excellent C-3-regioselectivity direct arylation.•A new method for the formation of CC bonds to prepare imidazo1,2-apyridines.
Background:
Talaromyces marneffei, also named Penicillium marneffei, is an opportunistic pathogen that can cause systemic or limited infection in human beings. This infection is especially common in ...human immunodeficiency virus (HIV)-infected hosts; however, it has also been recently reported in HIV-negative hosts. Here, we report a very rarely seen case of T. marneffei pulmonary infection in a non-HIV-infected patient with signal transducer and activator of transcription 3 (STAT3) mutation.
Case presentation:
A 34-year-old woman was admitted to our hospital for uncontrollable nonproductive cough and dyspnea with exercise. She had been immunocompromised since infancy. Computerized tomography scan showed multiple ground glass opacities with multiple bullae in both lungs. Next generation sequencing (NGS) of the bronchoalveolar lavage fluid identified T. marneffei nucleotide sequences. Culture of bronchoscopy specimens further verified the results. The patient was HIV negative, and blood gene detection indicated STAT3 mutation. To date, following the application of itraconazole, the patient has recovered satisfactorily.
Conclusion:
In clinical practice, T. marneffei infection among HIV-negative individuals is relatively rare, and we found that patients who are congenitally immunocompromised due to STAT3 mutation may be potential hosts. Early diagnosis and timely treatment are expected to improve the prognosis of T. marneffei infection. NGS is a powerful technique that may play an important role in this progress.
The reviews of this paper are available via the supplemental material section.
Genetic mapping to identify genes and alleles associated with or causing economically important quantitative trait variation in livestock animals such as pigs is a major goal in animal genetic ...improvement. Despite recent advances in high-throughput genotyping technologies, the resolution of genetic mapping in pigs remains poor due in part to the low density of genotyped variant sites. In this study, we overcame this limitation by developing a reference haplotype panel for pigs based on 2259 whole genome-sequenced animals representing 44 pig breeds. We evaluated software combinations and breed composition to optimize the imputation procedure and achieved an average concordance rate in excess of 96%, a non-reference concordance rate of 88%, and an r
of 0.85. We demonstrated in two case studies that genotype imputation using this resource can dramatically improve the resolution of genetic mapping. A public web server has been developed to allow the pig genetics community to fully utilize this resource. We expect this resource to facilitate genetic mapping and accelerate genetic improvement in pigs.
Dickeya dadantii is a common pathogen of bacterial soft rot on a wide range of plants, including several crops. In this study, we present the complete genome sequence of the D. dadantii type strain ...DSM18020T. The genome was assembled using PacBio technology, resulting in a 4,997,541 bp circular chromosome with a G+C content of 56.5%. Our sequence analyses predicted 4277 protein-encoding genes, including several associated with known bacterial virulence factors and secondary metabolites. Comparative genomics analysis between Dickeya revealed that the category of ‘metabolism’ is the most important in both the core and accessory genomes, while the category of ‘information storage and processing’ is the most dominant in unique genomes. These findings will not only help us to understand the pathogenic mechanisms of D. dadantii DSM18020T, but also provide us with useful information for new control strategies against this phytopathogen.
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