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Cannabis use is associated with cardiovascular adverse effects ranging from arrhythmias to sudden cardiac death. The exact mechanism of action behind these activities is unknown. The aim of our work was to study the effect of cannabidiol (CBD), tetrahydrocannabinol and 11-nor-9-carboxy-tetrahydrocannabinol on cellular cardiac electrophysiological properties including ECG parameters, action potentials, hERG and IKr ion channels in HEK cell line and in rabbit and guinea pig cardiac preparations. CBD increased action potential duration in rabbit and guinea pig right ventricular papillary muscle at lower concentrations (1 µM, 2.5 µM and 5 µM) but did not significantly change it at 10 µM. CBD at high concentration (10 µM) decreased inward late sodium and L-type calcium currents as well. CBD inhibited hERG potassium channels with an IC50 value of 2.07 µM at room temperature and delayed rectifier potassium current with 6.5 µM at 37 °C, respectively. The frequency corrected QT interval (QTc) was significantly lengthened in anaesthetized guinea pig without significantly changing other ECG parameters. Although the IC50 value of CBD was higher than literary Cmax values after CBD smoking and oral intake, our results raise the possibility that hERG and potassium channel inhibition might have a role in the possible proarrhythmic adverse effects of cannabinoids in situations where metabolism of CBD impaired and/or the repolarization reserve is weakened.To elucidate the molecular pathogenesis of pediatric germ cell tumors (GCTs), we performed DNA methylation array analysis, whole transcriptome sequencing, targeted capture sequencing, and single-nucleotide polymorphism array analysis using 51 GCT samples (25 female, 26 male), including 6 germinomas, 2 embryonal carcinomas, 4 immature teratomas, 3 mature teratomas, 30 yolk sac tumors, and 6 mixed germ cell tumors. Among the 51 samples, 11 were from infants, 23 were from young children, and 17 were from those aged ≥10 years. Sixteen of the 51 samples developed in the extragonadal regions. Germinomas showed upregulation of pluripotent genes and global hypomethylation. Pluripotent genes were also highly expressed in embryonal carcinomas. These genes may play essential roles in embryonal carcinomas given that their binding sites are hypomethylated. Yolk sac tumors exhibited overexpression of endodermal genes, such as GATA6 and FOXA2, the binding sites of which were hypomethylated. Interestingly, infant yolk sac tumors had different DNA methylation patterns from those observed in older children. Teratomas had higher expression of ectodermal genes, suggesting a tridermal nature. Based on our results, we suggest that KIT, TNFRSF8, and ERBB4 may be suitable targets for the treatment of germinoma, embryonal carcinomas, and yolk sac tumors, respectively.Chronic inflammatory lung diseases impact more than 300 million of people worldwide. Because they are not curable, these diseases have a high impact on both the quality of life of patients and the healthcare budget. The stability of patient condition relies mostly on constant treatment adaptation and lung function monitoring. However, due to the variety of inflammation phenotypes, almost one third of the patients receive an ineffective treatment. To improve phenotyping, we evaluated the complementarity of two techniques for exhaled breath analysis full resolving comprehensive two-dimensional gas chromatography coupled to high-resolution time-of-flight mass spectrometry (GC × GC-HRTOFMS) and rapid screening selected ion flow tube MS (SIFT-MS). GC × GC-HRTOFMS has a high resolving power and offers a full overview of sample composition, providing deep insights on the ongoing biology. SIFT-MS is usually used for targeted analyses, allowing rapid classification of samples in defined groups. In this study, we used SIFT-MS in a possible untargeted full-scan mode, where it provides pattern-based classification capacity. We analyzed the exhaled breath of 50 asthmatic patients. Enzalutamide datasheet Both techniques provided good classification accuracy (around 75%), similar to the efficiency of other clinical tools routinely used for asthma phenotyping. Moreover, our study provides useful information regarding the complementarity of the two techniques.Identification of pathogens causing viral encephalitis remains challenging, and in over 50% of cases the etiologic factor remains undetermined. Next-generation sequencing (NGS) based metagenomics has been successfully used to detect novel and rare infections, but its value for routine diagnosis of encephalitis remains unclear. The aim of the present study was to determine the sensitivity of shotgun metagenomic sequencing protocols, which include preamplification, and testing it against cerebrospinal fluid (CSF) samples from encephalitis patients. For sensitivity testing HIV and HBV positive sera were serially diluted in CSF from an uninfected patient. NGS repeatedly detected HIV and HBV sequences present at concentrations from 105 to 102 and from 105 to 10 viral copies/reaction, respectively. However, when the same protocols were applied to RT-PCR/PCR positive CSF samples from 6 patients with enteroviral encephalitis (median viral load 47 copies/ml) and 15 patients with HSV, CMV or VZV encephalitis (median viral load 148 copies/ml), only 7 (28.6%) were identified as positive. In conclusions, while NGS has the advantage of being able to identify a wide range of potential pathogens it seems to be less sensitive compared to the standard amplification-based assays in the diagnosis of encephalitis, where low viral loads are common.An amendment to this paper has been published and can be accessed via a link at the top of the paper.Ecologically relevant genes generally show patchy distributions among related bacterial genomes. This is commonly attributed to lateral gene transfer, whereas the opposite mechanism-gene loss-has rarely been explored. Pseudogenization is a major mechanism underlying gene loss, and pseudogenes are best characterized by comparing closely related genomes because of their short life spans. To explore the role of pseudogenization in microbial ecological diversification, we apply rigorous methods to characterize pseudogenes in the 279 newly sequenced Ruegeria isolates of the globally abundant Roseobacter group collected from two typical coastal habitats in Hong Kong, the coral Platygyra acuta and the macroalga Sargassum hemiphyllum. Pseudogenes contribute to ~16% of the accessory genomes of these strains. Ancestral state reconstruction reveals that many pseudogenization events are correlated with ancestral niche shifts. Specifically, genes related to resource scavenging and energy acquisition were often pseudogenized when roseobacters inhabiting carbon-limited and energy-poor coral skeleton switched to other resource-richer niches.
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