Streptococcus pneumoniae (Spn) is a common pathogen for pediatric pneumonia and leads to severe lung injury. This study is conducted to analyze the role of F-box and leucine rich repeat protein 19 (FBXL19) in Spn-induced lung injury in immature mice.Immature mice were infected with Spn to record the survival rates and bacterial loads in bronchoalveolar lavage fluid. Levels of FBXL19 and FOXM1 in lung tissues were determined via real-time quantitative polymerase chain reaction or Western blotting. After the interference of FBXL19, its impacts on lung inflammatory injury were appraised by the lung wet/dry weight ratio, myeloperoxidase activity, hematoxylin and eosin staining, and enzyme-linked immunosorbent assay. The binding of FBXL19 to forkhead box M1 (FOXM1) in mouse lung epithelial cells was determined. After MG132 treatment, the protein and ubiquitination levels of FOXM1 were measured. The functional rescue experiments were performed to analyze the role of FOXM1 in FBXL19-regulated lung injury.FBXL19 was downregulated while FOXM1 was upregulated in lung tissues of Spn-infected immature mice. Overexpression of FBXL19 reduced the degree of lung injury and inflammation. FBXL19 can bind to FOXM1 to reduce its protein level via ubiquitination degradation. MG132 reduced the ubiquitination and increased the protein level of FOXM1. Overexpression of FOXM1 reversed the protective role of FBXL19 overexpression in lung injury of Spn immature mice.FBXL19 was downregulated by Spn and FBXL19 overexpression alleviated lung injury by inducing ubiquitination and degradation of FOXM1 in Spn immature mice.
Abstract Background To successfully replicate within the host cell, Toxoplasma gondii employs several mechanisms to overcome the host cell defenses and mitigate the harmful effects of the free radicals resulting from its own metabolic processes using effectors such as thioredoxin proteins. In this study, we characterize the location and functions of a newly identified thioredoxin in T. gondii , which was named Trx4. Methods We characterized the functional role of Trx4 in T. gondii Type I RH and Type II Pru strains by gene knockout and studied its subcellular localization by endogenous protein HA tagging using CRISPR-Cas9 gene editing. The enzyme-catalyzed proximity labeling technique, the TurboID system, was employed to identify the proteins in proximity to Trx4. Results Trx4 was identified as a dense granule protein of T. gondii predominantly expressed in the parasitophorous vacuole (PV) and was partially co-localized with GRA1 and GRA5. Functional analysis showed that deletion of trx4 markedly influenced the parasite lytic cycle, resulting in impaired host cell invasion capacity in both RH and Pru strains. Mutation of Trx domains in Trx4 in RH strain revealed that two Trx domains were important for the parasite invasion. By utilizing the TurboID system to biotinylate proteins in proximity to Trx4, we identified a substantial number of proteins, some of which are novel, and others are previously characterized, predominantly distributed in the dense granules. In addition, we uncovered three novel proteins co-localized with Trx4. Intriguingly, deletion of trx4 did not affect the localization of these three proteins. Finally, a virulence assay demonstrated that knockout of trx4 resulted in a significant attenuation of virulence and a significant reduction in brain cyst loads in mice. Conclusions Trx4 plays an important role in T. gondii invasion and virulence in Type I RH strain and Type II Pru strain. Combining the TurboID system with CRISPR-Cas9 technique revealed many PV-localized proximity proteins associated with Trx4. These findings suggest a versatile role of Trx4 in mediating the processes that occur in this distinctive intracellular membrane-bound vacuolar compartment. Graphical Abstract
The gut microbiota has been linked to cardiovascular diseases. However, the composition and functional capacity of the gut microbiome in relation to cardiovascular diseases have not been systematically examined. Here, we perform a metagenome-wide association study on stools from 218 individuals with atherosclerotic cardiovascular disease (ACVD) and 187 healthy controls. The ACVD gut microbiome deviates from the healthy status by increased abundance of Enterobacteriaceae and Streptococcus spp. and, functionally, in the potential for metabolism or transport of several molecules important for cardiovascular health. Although drug treatment represents a confounding factor, ACVD status, and not current drug use, is the major distinguishing feature in this cohort. We identify common themes by comparison with gut microbiome data associated with other cardiometabolic diseases (obesity and type 2 diabetes), with liver cirrhosis, and rheumatoid arthritis. Our data represent a comprehensive resource for further investigations on the role of the gut microbiome in promoting or preventing ACVD as well as other related diseases.The gut microbiota may play a role in cardiovascular diseases. Here, the authors perform a metagenome-wide association study on stools from individuals with atherosclerotic cardiovascular disease and healthy controls, identifying microbial strains and functions associated with the disease.
In this study, the mitochondrial genome of Acanthogobius hasta was fully sequenced compared to other fish species mitochondrial genome. The genome is 16,659 bp in length, including 2 ribosomal RNA genes, 13 protein-coding genes (PCGs), 22 transfer RNA genes, and a non-coding control region, the gene composition and order of which was similar to most reported from other vertebrates. Sequence analysis showed that the overall base composition is 27.8% for A, 28.0% for C, 17.4% for G, and 26.9% for T.
To analyze the enrichment pathway, hub gene, and Protein-protein interaction (PPI) network of rheumatoid arthritis (RA) and construct peripheral blood subtypes based on integrated bioinformatics analysis.
Rabproteins are the largest members of the small G protein family and are widely distributed in eukaryotes. It comprises eight subfamilies and is responsible for regulating vesicle transport, plant growth and development, and biotic and abiotic stress responses. In this study, the small G protein gene StRab5b was cloned from potato, and its biological information, expression profile and induced expression level, overexpression and gene silencing were examined on regulating potato resistance to Phytophthora infestans using PCR, qPCR and Virus-induced gene silencing (VIGS). Our results indicate that the amino acid of StRab5b shows the highest and lowest homology with NbRab5b in N. benthamiana and StRab in potato respectively. StRab5b expression varied among different potato tissues and varieties, and was induced by P. infestans infection. Transiently ectopic expression of StRab5b in N. benthamiana enhanced its resistance to P. infestans, whereas, silencing of StRab5b and its homologous gene facilitated pathogen infection in potato and N. benthamiana respectively. Furthermore, stable expression of the StRab5b gene in potatoes enhanced its redox-stress response capacity, as manifested by the accumulation of H2O2 in infected leaves and subsequent increase in the activity and expression of ROS scavenging enzymes, thereby attenuating the development of P. infestans and ultimately reducing the lesions on infected potato leaves. In addition, the LOX gene transcripts and JA level were upregulated rapidly after inoculation with P. infestans. Collectively, our results suggest that StRab5b positively regulates the resistance against potato late blight (PLB) via JA-mediated defense signaling pathway.
Phenotypic switching between tachyzoite and bradyzoite is the fundamental mechanism underpinning the pathogenicity and adaptability of the protozoan parasite Toxoplasma gondii. Although accumulation of cytoplasmic starch granules is a hallmark of the quiescent bradyzoite stage, the regulatory factors and mechanisms contributing to amylopectin storage in bradyzoites are incompletely known. Here, we show that T. gondii protein phosphatase 2A (PP2A) holoenzyme is composed of a catalytic subunit PP2A-C, a scaffold subunit PP2A-A and a regulatory subunit PP2A-B. Disruption of any of these subunits increased starch accumulation and blocked the tachyzoite-to-bradyzoite differentiation. PP2A contributes to the regulation of amylopectin metabolism via dephosphorylation of calcium-dependent protein kinase 2 at S679. Phosphoproteomics identified several putative PP2A holoenzyme substrates that are involved in bradyzoite differentiation. Our findings provide novel insight into the role of PP2A as a key regulator of starch metabolism and bradyzoite differentiation in T. gondii.
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