Biallelic loss of function variants in PPP1R21 cause a neurodevelopmental syndrome with impaired endocytic function

Next‐generation sequencing (NGS) has been instrumental in solving the genetic basis of rare inherited diseases, especially neurodevelopmental syndromes. However, functional workup is essential for precise phenotype definition and to understand the underlying disease mechanisms. Using whole exome (WES) and whole genome sequencing (WGS) in four independent families with hypotonia, neurodevelopmental delay, facial dysmorphism, loss of white matter, and thinning of the corpus callosum, we identified four previously unreported homozygous truncating PPP1R21 alleles: c.347delT p.(Ile116Lysfs*25), c.2170_2171insGGTA p.(Ile724Argfs*8), c.1607dupT p.(Leu536Phefs*7), c.2063delA p.(Lys688Serfs*26) and found that PPP1R21 was absent in fibroblasts of an affected individual, supporting the allele's loss of function effect. PPP1R21 function had not been studied except that a large scale affinity proteomics approach suggested an interaction with PIBF1 defective in Joubert syndrome. Our co‐immunoprecipitation studies did not confirm this but in contrast defined the localization of PPP1R21 to the early endosome. Consistent with the subcellular expression pattern and the clinical phenotype exhibiting features of storage diseases, we found patient fibroblasts exhibited a delay in clearance of transferrin‐488 while uptake was normal. In summary, we delineate a novel neurodevelopmental syndrome caused by biallelic PPP1R21 loss of function variants, and suggest a role of PPP1R21 within the endosomal sorting process or endosome maturation pathway.     

Pharmacokinetics of single oral and multiple intravenous and oral administration of acebutolol enantiomers in a rat model

Acebutolol (AC), is a chiral, β -adrenergic blocking agent which possesses partial agonist activity and is metabolized to an equipotent chiral metabolite, diacetolol (DC). The enantiomeric disposition of AC is reported following racemic administration as a single oral (p.o., 50 mg kg⁻¹) or as a multiple thrice daily intravenous (i.v.) or p.o. dosing for four days in male Sprague–Dawley rats (n =6). Enantiomeric concentrations of AC and DC in plasma and urine were determined using a stereospecific HPLC assay. The bioavailabilities of R- and S-enantiomer were 0.40 and 0.39 after single dose administration of AC respectively. These values were increased to 0.51 and 0.53 after multiple dosing. Although no significant differences were found in AUC_0–∞ after single i.v. as compared with AUC_0–τ after multiple i.v. dosing of AC, the 39 and 45% increase in mean AUC_0–τ were found after multiple p.o. dosing over the corresponding AUC_0–∞, for the single p.o. dose of AC for R- and S-enantiomer, respectively. The disposition of DC as well as the urinary excretion of metabolite was stereoselective in favor of R-enantiomer after oral administration of AC. These results indicate that AC enantiomers have low availability and moderate extraction through the first-pass metabolism in a rat model. The higher AUC values after p.o. multiple dosing may suggest a saturable first-pass metabolism of AC. © 1998 John Wiley & Sons, Ltd.     

Spatiotemporal analysis,hotspot mapping,and clustering of confirmed cases of COVID-19 in the initial phase of the pandemic in Qom province,Iran

Objective: To identify the incidence rate, relative risk, hotspot regions and incidence trend of COVID-19 in Qom province, northwest part of Iran in the first stage of the pandemic.Methods: The study included 1125 officially reported PCR-confirmed cases of COVID-19 from 20 February 2020 to 20 April 2020 in 90 regions in Qom city, Iran. The Bayesian hierarchical spatial model was used to model the relative risk of COVID-19 in Qom city, and the segmented regression model was used to estimate the trend of COVID-19 incidence rate. The Poisson distribution was applied for the observed number of COVID-19, and independent Gamma prior was used for inference on log-relative risk parameters of the model. Results: The total incidence rate of COVID-19 was estimated at 89.5 per 100000 persons in Qom city (95％ CI: 84.3, 95.1). According to the results of the Bayesian hierarchical spatial model and posterior probabilities, 43.33％ of the regions in Qom city have relative risk greater than 1; however, only 11.11％ of them were significantly greater than 1. Based on Geographic Information Systems (GIS) spatial analysis, 10 spatial clusters were detected as active and emerging hotspot areas in the south and central parts of the city. The downward trend was estimated 10 days after the reporting of the first case (February 7, 2020); however, the incidence rate was decreased by an average of 4.24％ per day (95％ CI: ?10.7, ?3.5). Conclusions: Spatial clusters with high incidence rates of COVID-19 in Qom city were in the south and central regions due to the high population density. The GIS could depict the spatial hotspot clusters of COVID-19 for timely surveillance and decision-making as a way to contain the disease.     

Increased functional connectivity in the ventral and dorsal streams during retrieval of novel words in professional musicians

Current models of speech and language processing postulate the involvement of two parallel processing streams (the dual stream model): a ventral stream involved in mapping sensory and phonological representations onto lexical and conceptual representations and a dorsal stream contributing to sound‐to‐motor mapping, articulation, and to how verbal information is encoded and manipulated in memory. Based on previous evidence showing that music training has an influence on language processing, cognitive functions, and word learning, we examined EEG‐based intracranial functional connectivity in the ventral and dorsal streams while musicians and nonmusicians learned the meaning of novel words through picture–word associations. In accordance with the dual stream model, word learning was generally associated with increased beta functional connectivity in the ventral stream compared to the dorsal stream. In addition, in the linguistically most demanding “semantic task,” musicians outperformed nonmusicians, and this behavioral advantage was accompanied by increased left‐hemispheric theta connectivity in both streams. Moreover, theta coherence in the left dorsal pathway was positively correlated with the number of years of music training. These results provide evidence for a complex interplay within a network of brain regions involved in semantic processing and verbal memory functions, and suggest that intensive music training can modify its functional architecture leading to advantages in novel word learning.     

Blockade of orexin receptor 1 attenuates the development of morphine tolerance and physical dependence in rats

The goals of this study were to evaluate the effects of pretreatment by orexin receptor-1 antagonist on the development of morphine tolerance and physical dependence in rat. Animals were rendered dependent on morphine by subcutaneous (SC) injection of morphine sulfate (10 mg/kg) at set intervals of 12 h for 10 days. Just before the morphine administration, the animals received SB-334867, a selective orexin receptor 1 (OXR1) antagonist. To assess morphine tolerance, the antinociceptive responses of morphine were measured using the warm-water tail immersion test before and after its administration. On day 11, naloxone was injected 2 h after morphine administration and the physical dependence evaluated by quantifying/scoring naloxone-precipitated withdrawal signs for 30 min. The effect of chronic SB-334867 on locomotion was carried out by calculating the number of grid crossings as a measure of locomotor activity. Our findings demonstrated that although morphine-tolerance tended to develop in response to repeated injections of morphine, pre-treatment of OXR1 antagonist prevented this effect, causing a delay in the development of morphine-tolerance. Moreover, co-administration of orexin receptor 1 antagonist with morphine significantly decreased the somatic signs of withdrawal including diarrhea, teeth chattering, jumping, and defecation. Administration of SB-334867 alone or in a chronic co-administration with morphine failed to change locomotor activity. These results suggest that the activation of OXR1 might be involved in the development of morphine tolerance and dependence.     

Effects of pentaerythritol tetranitrate on endothelial function in coronary artery disease: results of the PENTA study

Background  

Pentaerythritol tetranitrate (PETN) differs from other organic nitrates by the lack of tolerance induction and by antioxidative properties. The purpose of this study was to determine the effect of PETN on endothelial function in patients with coronary artery disease (CAD). We hypothesized that the treatment with PETN improves endothelial function in patients with CAD.