Pharmacokinetics and safety evaluation of intravenously administered Pseudomonas phage PA_LZ7 in a mouse model.

IMPORTANCE: Phage therapy is gaining traction as an alternative to antibiotics due to the rise of multi-drug-resistant (MDR) bacteria. This study assessed the pharmacokinetics and safety of PA_LZ7, a phage targeting MDR Pseudomonas aeruginosa, in mice. After intravenous administration, the phage showed an exponential decay in plasma and its concentration dropped significantly within 24 h for all dosage groups. Although there was a temporary increase in certain plasma cytokines and spleen weight at higher dosages, no significant toxicity was observed. Therefore, PA_LZ7 shows potential as an effective and safe candidate for future phage therapy against MDR P. aeruginosa infections.

Mutation spectrum in a cohort with familial exudative vitreoretinopathy.

PURPOSE: To expand the mutation spectrum of patients with familial exudative vitreoretinopathy (FEVR) disease. PARTICIPANTS: 74 probands (53 families and 21 sporadic probands) with familial exudative vitreoretinopathy (FEVR) disease and their available family members (n = 188) were recruited for sequencing. METHODS: Panel-based targeted screening was performed on all subjects. Before sanger sequencing, variants of LRP5, NDP, FZD4, TSPAN12, ZNF408, KIF11, RCBTB1, JAG1, and CTNNA1 genes were verified by a series of bioinformatics tools and genotype-phenotype co-segregation analysis. RESULTS: 40.54% (30/74) of the probands were sighted to possess at least one etiological mutation of the nine FEVR-causative genes. The etiological mutation detection rate was 37.74% (20/53) in family-attainable probands while 47.62% (10/21) in sporadic cases. The diagnosis rate of patients in the early-onset subgroup (≤5 years old, 45.4%) is higher than that of the children or adolescence-onset subgroup (6-16 years old, 42.1%) and the late-onset subgroup (≥17 years old, 39.4%). A total of 36 etiological mutations were identified in this study, comprising 26 novel mutations and 10 reported mutations. LRP5 was the most prevalent mutant gene among the 36 mutation types with a percentage of 41.67% (15/36). Followed by FZD4 (10/36, 27.78%), TSPAN12 (5/36, 13.89%), NDP (4/36, 11.11%), KIF11 (1/36, 2.78%), and RCBTB1 (1/36, 2.78%). Among these mutations, 63.89% (23/36) were missense mutations, 25.00% (9/36) were frameshift mutations, 5.56% (2/36) were splicing mutations, 5.56% (2/36) were nonsense mutations. Moreover, the clinical pathogenicity of these variants was defined according to American College of Medical Genetics (ACMG) and genomics guidelines: 41.67% (15/36) were likely pathogenic variants, 27.78% (10/36) pathogenic variants, 30.55% (11/36) variants of uncertain significance. No etiological mutations discovered in the ZNF408, JAG1, and CTNNA1 genes in this FEVR cohort. CONCLUSIONS: We systematically screened nine FEVR disease-associated genes in a cohort of 74 Chinese probands with FEVR disease. With a detection rate of 40.54%, 36 etiological mutations of six genes were authenticated in 30 probands, including 26 novel mutations and 10 reported mutations. The most prevalent mutated gene is LRP5, followed by FZD4, TSPAN12, NDP, KIF11, and RCBTB1. In total, a de novo mutation was confirmed. Our study significantly clarified the mutation spectrum of variants bounded up to FEVR disease.

Global transcriptome profiling reveals antagonizing response of head kidney of juvenile common carp exposed to glyphosate.

Glyphosate (GLY) frequently detected in various water bodies has imposed a serious risk on fish. Head kidney of fish is an important defense organ, playing a vital part in antagonizing exogenous hazardous matter. The objective of this study was to characterize toxic mechanisms of GLY in head kidney of common carp based on transcriptome profiling. After 45-days exposure of GLY at environmentally relevant concentrations, juvenile common carp were used as experimental subjects to analyze how the head kidney responded to GLY. The transcriptome profiling identified 1381 different expressed genes (DEGs) between the control and exposure groups (5 and 50 mg/L). Functional analysis of DEGs substantiated over-representative pathways mainly involving cellular stress responses, cell proliferation and turnover, apoptosis, lipid metabolism, and innate immune processes in both treated groups compared with the control group. Predicted network of gene regulation indicated that GLY-induced tp53 played a vital role in linking a battery of signals. Furthermore, the expression of 10 candidate genes by qRT-PCR aligned with transcriptional profiling. In addition, western blotting analysis confirmed that GLY-induced apoptosis and cellular proliferation were closely involved in activating MAKP signaling pathway and lipid metabolism pathway in both treated groups. Collectively, these data demonstrate that head kidney of juvenile common carp mainly leverages upregulation of genes related to cell proliferation and turnover, apoptosis, and lipid metabolism to combat sub-chronic exposure of GLY. This study casts new understanding into the risk of GLY in aquatic animals.