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Although in recent years there has been intensification in the use of nanoparticles (NPs) for the production of many commercial products, few studies have been carried out to assess the risks associated with its use. Among the most used NPs, silver nanoparticles (AgNPs) have a preponderant position as they have various applications. In this study, 40 adult zebrafish were exposed to increasing concentrations of AgNPs (8, 45, and 70 mu g/L) for 30 days to evaluate the effects on eyes after chronic exposure to AgNPs with an average diameter of 50 nm. From the morphological and ultrastructural analysis performed, no alteration or lesions of the corneal epithelium were detected.

The outbreak of severe pneumonia due to the new SARS‐CoV‐2 has created a world emergency that is putting global public health institutions at high alert. Since the first official paper on January 20 up to now more than 10.000 publications have appeared on PubMed. Surprisingly, no single paper has been dealing with the potential impact of the COVID‐19 on Down Syndrome (DS). As COVID‐19 presents as an acute severe respiratory syndrome and DS is by far the most frequent chromosomal disease with the highest susceptibility to develop respiratory infections and complications (1), it seems timely to focus on this syndrome during the ongoing pandemic.

Discovered as a modulator of the toxic response to environmental pollutants, aryl hydrocarbon receptor (AhR) has recently gained attention for its involvement in various physiological and pathological pathways. AhR is a ligand-dependent transcription factor activated by a large array of chemical compounds, which include metabolites of l-tryptophan (l-Trp) catabolism as endogenous ligands of the receptor. Among these, 2-(1'H-indole-3'-carbonyl)thiazole-4-carboxylic acid methyl ester (ITE) has attracted interest in the scientific community, being endowed with nontoxic, immunomodulatory, and anticancer AhR-mediated functions. So far, no information about the binding mode and interactions of ITE with AhR is available. In this study, we used docking and molecular dynamics to propose a putative binding mode of ITE into the ligand binding pocket of AhR. Mutagenesis studies were then instrumental in validating the proposed binding mode, identifying His 285 and Tyr 316 as important key residues for ligand-dependent receptor activation. Finally, a set of ITE analogues was synthesized and tested to further probe molecular interactions of ITE to AhR and characterize the relevance of specific functional groups in the chemical structure for receptor activity.

Insulin degludec is an extra‐long‐acting insulin analog that allows for enhanced efficacy and flexibility in the injection time. However, it is not approved for use during pregnancy. We report the pregnancy outcome and newborn conditions in two women with type 1 diabetes who continued preconception degludec treatment during embryogenesis. No pregnancy complication or congenital neonatal malformation was observed. Both babies presented with hypoglycemia and required neonatal intensive care unit admission. Degludec treatment did not cause adverse effects in the mothers or malformations in the newborns. The observed neonatal complications were probably independent of early pregnancy degludec treatment.

BackgroundOsteogenesis imperfecta (OI) is a heterogeneous bone disorder characterized by recurrent fractures. Although most cases of OI have heterozygous mutations in COL1A1 or COL1A2 and show autosomal dominant inheritance, during the last years there has been an explosion in the number of genes responsible for both recessive and dominant forms of this condition. Herein, we have analyzed a cohort of patients with OI, all offspring of unaffected parents, to determine the spectrum of variants accounting for these cases. Twenty patients had nonrelated parents and were sporadic, and 21 were born to consanguineous relationships. MethodsMutation analysis was performed using a next-generation sequencing gene panel, homozygosity mapping, and whole exome sequencing (WES). ResultsPatients offspring of nonconsanguineous parents were mostly identified with COL1A1 or COL1A2 heterozygous changes, although there were also a few cases with IFITM5 and WNT1 heterozygous mutations. Only one sporadic patient was a compound heterozygote for two recessive mutations. Patients offspring of consanguineous parents showed homozygous changes in a variety of genes including CRTAP, FKBP10, LEPRE1, PLOD2, PPIB, SERPINF1, TMEM38B, and WNT1. In addition, two patients born to consanguineous parents were found to have de novo COL1A1 heterozygous mutations demonstrating that causative variants in the collagen I structural genes cannot be overlooked in affected children from consanguineous couples. Further to this, WES analysis in probands lacking mutations in OI genes revealed deleterious variants in SCN9A, NTRK1, and SLC2A2, which are associated with congenital indifference to pain (CIP) and Fanconi-Bickel syndrome (FBS). ConclusionThis work provides useful information for clinical and genetic diagnosis of OI patients with no positive family history of this disease. Our data also indicate that CIP and FBS are conditions to be considered in the differential diagnosis of OI and suggest a positive role of SCN9A and NTRK1 in bone development.

Background and purpose: Cannabidiol is a Cannabis-derived non-psychotropic compound that exerts a plethora of pharmacological actions, including anti-inflammatory, neuroprotective and antitumour effects, with potential therapeutic interest. However, the actions of cannabidiol in the digestive tract are largely unexplored. In the present study, we investigated the effect of cannabidiol on intestinal motility in normal (control) mice and in mice with intestinal inflammation. Experimental approach: Motility in vivo was measured by evaluating the distribution of an orally administered fluorescent marker along the small intestine; intestinal inflammation was induced by the irritant croton oil; contractility in vitro was evaluated by stimulating the isolated ileum, in an organ bath, with ACh. Key results: In vivo, cannabidiol did not affect motility in control mice, but normalized croton oil-induced hypermotility. The inhibitory effect of cannabidiol was counteracted by the cannabinoid CB1 receptor antagonist rimonabant, but not by the cannabinoid CB2 receptor antagonist SR144528 (N-[-1S-endo-1,3,3-trimethyl bicyclo [2.2.1] heptan-2-yl]-5-(4-chloro3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide), by the opioid receptor antagonist naloxone or by the a2-adrenergic antagonist yohimbine. Cannabidiol did not reduce motility in animals treated with the fatty acid amide hydrolase (FAAH) inhibitor N-arachidonoyl-5-hydroxytryptamine, whereas loperamide was still effective. In vitro, cannabidiol inhibited ACh-induced contractions in the isolated ileum from both control and croton oil-treated mice. Conclusions and implications: Cannabidiol selectively reduces croton oil-induced hypermotility in mice in vivo and this effect involves cannabinoid CB1 receptors and FAAH. In view of its low toxicity in humans, cannabidiol may represent a good candidate to normalize motility in patients with inflammatory bowel disease. British Journal of Pharmacology (2008) 154, 1001–1008; doi:10.1038/bjp.2008.177; published online 12 May 2008

The effect of crude extracts (CEs) of virulent (V-E4) and hypovirulent (H-E13) Cryphonectria parasitica strains on growth and physiological activities of chestnut calli was investigated on cell cultures obtained from either a susceptible Castanea sativa or a resistant Castanea mollissima chestnut species. The V-E4 CEs significantly reduced calli fresh weight in both species when used at 50 and 500 μg g–1 and, in general, showed an inhibitory effect on either O2 uptake and H+-ATPase activity. Only the highest (500 μg g–1) concentration of H-E13 CEs had a detrimental effect on callus growth, whereas the lowest one (5 μg g–1) induced a slight, but significant early increase in callus fresh weight of both genotypes. The O2 uptake and H+-ATPase activity were enhanced by the presence of H-E13 CEs. The decrease of callus growth and physiological activities, caused by V-E4 CEs, was attributed to toxic compounds produced by the C. parasitica virulent strain, whereas the stimulatory effects of H-E13 CEs on the overall callus metabolism seemed to be due either to the lack or very reduced amount of phytotoxic compounds and to growth-regulating substances produced only by the hypovirulent strain of the fungus. Croissance et activites physiologiques des cals de châtaignier exposes aux extraits bruts de souches virulente et hypovirulente de Cryphonectria parasitica L'effet des extraits bruts (EBs) de la souche virulente (V-E4) et de la souche hypovirulente (H-E13) de Cryphonectria parasitica a eteetudie soit sur une espece susceptible, Castanea sativa, soit sur une espece resistante, Castanea mollissima, de châtaignier. Les EBs de V-E4, utilises aux doses de 50 et 500 μg g–1, ont reduit significativement le poids frais des cals des deux especes et ont montre en general un effet negatif sur l'absorption d'oxygene et l'activite de l'H+-ATPase. Au contraire, les Ebs de H-E13 ont induit une legere, mais significative augmentation de la croissance des cals des deux genotypes et, au meme temps, des parametres physiologiques. La reduction de la croisance des cals et des activites physiologiques, provoquee par les EBs de V-E4, a ete attribuee a des composes toxiques produits par la souche virulente de C. parasitica, tandis que l'effet positif exerce par les EBs de H-E13 sur le metabolisme des cals, est probablement dua l'absence ou a la quantite tres reduite de composes toxiques et aux substances regulatrices de la croissance produite par la souche hypovirulente du châmpignon. Wirkung von Rohextrakten aus einem virulenten und einem hypovirulenten Stamm von Cryphonectria parasitica auf das Wachstum und das physiologische Verhalten von Kastanienkalli Wirkungen von Rohextrakten (CEs) von einem virulenten (V-E4) und einem hypovirulenten (H-E13) Stamm von Cryphonectria parasitica auf das Wachstum und verschiedene physiologische Parameter von Kastanienkalli wurden an der anfalligen Art Castanea sativa sowie an der resistenten Art Castanea mollissima untersucht. V-E4 CEs reduzierten das Frischgewicht der Kalli von beiden Kastanienarten signifikant bei Konzentrationen von 50 und 500 μg g–1 und hemmten allgemein die O2-Aufnahme und die H+-ATPase-Aktivitat. Nur die hochste Konzentration (500 μg g–1) der H-E13 CEs wirkte negativ auf das Kalluswachstum, wahrend die geringste (5 μg g–1) eine leichte, aber signifikante Zunahme des Kallus-Frischgewichts bei beiden Genotypen induzierte. Die O2-Aufnahme und die H+-ATPase-Aktivitat war unter Einwirkung von H-E13 CEs erhoht. Die Abnahme des Kalluswachstums und der physiologischen Aktivitat, die durch V-E4 CEs verursacht wurde, wird auf toxische Verbindungen zuruckgefuhrt, die von dem virulenten C. parasitica-Stamm gebildet wurden. Die insgesamt stimulierenden Effekte der H-E13 CEs auf den Kallus-Metabolismus sind wahrscheinlich entweder auf das Fehlen oder die stark reduzierte Konzentration der phytotoxischen Substanzen oder aber auf die Produktion von wachstumsregulierenden Substanzen durch den hypovirulenten Pilzstamm zuruckzufuhren.