<i>GRIN2A</i>-related disorders:genotype and functional consequence predict phenotype

Alterations of the N-methyl-d-aspartate receptor (NMDAR) subunit GluN2A, encoded by GRIN2A, have been associated with a spectrum of neurodevelopmental disorders with prominent speech-related features, and epilepsy. We performed a comprehensive assessment of phenotypes with a standardized questionnaire in 92 previously unreported individuals with GRIN2A-related disorders. Applying the criteria of the American College of Medical Genetics and Genomics to all published variants yielded 156 additional cases with pathogenic or likely pathogenic variants in GRIN2A, resulting in a total of 248 individuals. The phenotypic spectrum ranged from normal or near-normal development with mild epilepsy and speech delay/apraxia to severe developmental and epileptic encephalopathy, often within the epilepsy-aphasia spectrum. We found that pathogenic missense variants in transmembrane and linker domains (misTMD+Linker) were associated with severe developmental phenotypes, whereas missense variants within amino terminal or ligand-binding domains (misATD+LBD) and null variants led to less severe developmental phenotypes, which we confirmed in a discovery (P = 10-6) as well as validation cohort (P = 0.0003). Other phenotypes such as MRI abnormalities and epilepsy types were also significantly different between the two groups. Notably, this was paralleled by electrophysiology data, where misTMD+Linker predominantly led to NMDAR gain-of-function, while misATD+LBD exclusively caused NMDAR loss-of-function. With respect to null variants, we show that Grin2a+/- cortical rat neurons also had reduced NMDAR function and there was no evidence of previously postulated compensatory overexpression of GluN2B. We demonstrate that null variants and misATD+LBD of GRIN2A do not only share the same clinical spectrum (i.e. milder phenotypes), but also result in similar electrophysiological consequences (loss-of-function) opposing those of misTMD+Linker (severe phenotypes; predominantly gain-of-function). This new pathomechanistic model may ultimately help in predicting phenotype severity as well as eligibility for potential precision medicine approaches in GRIN2A-related disorders

Theoretical and experimental vibrational study of phenylurea: structure, solvent effect and inclusion process with the β-cyclodextrin in the solid state

FTIR and Raman vibrational spectroscopic techniques as well as DFT quantum chemical calculation were used for characterizing conformational changes of phenylurea (a herbicide parent molecule) occurring from solid state to aqueous medium. Experimental infrared frequencies were assigned on the base of urea and benzenic derivatives spectroscopic data available in the literature and vibrational normal modes analytical calculation at the fully optimized geometry. Investigation of isotopic and solvent effects has revealed that the structure of phenylurea is particularly sensitive to the electrostatic environment via hydrogen non covalent bonds. The ability of β-cyclodextrin (β-CD) to form host–guest inclusion complex with phenylurea in the solid state was also evidenced by significant frequency shifts observed in the 1400–1800 cm−1 spectral range

Evolution of sinonasal clinical features in children with cystic fibrosis

International audienceObjective: to assess the evolution of sinonasal manifestations in children with cystic fibrosis, since the improvement of their prognosis over the last decades.Methods: an observational, monocentric study with a retrospective cohort. We included 173 children (from 4 to 18 years old) with cystic fibrosis followed at the pediatric cystic fibrosis center of lyon, france. We collected respiratory, infectious and nutritional data, sinonasal complaints and physical examination at the onset of sinonasal symptoms (t-0), at the most severe of evolution (t-max) and at the end of followup (t-end).Results: sinonasal symptomatology appeared early around 5.4 years old, then rapidly reached the maximum at 6.9 years and finally improved during childhood (p < 0.0001), reaching scores at t-end significantly better than at t-0 (p < 0.0001). This evolution was significant for nasal obstruction, rhinorrhea and snoring. The other symptoms were rarer, with no significant 38,7% at t-max (p < 0.0001), and 29,5% at t-end (p = 0.52). The lildholdt score, turbinate hypertrophy and medial bulging of medial wall of the maxillary sinus followed the same evolution (p < 0.003). There was no association between sinonasal evolution and cystic fibrosis disease at infectious, respiratory or nutritional level.Conclusion: it is the only recent study evaluating the evolution of each sinonasal manifestations in children with cystic fibrosis. Rhinosinusitis improved during childhood, reaching better scores than at the beginning of management. This particular improvement may be related to good effectiveness to ent management, but also to a positive effect of nasal cavity growth, independently to extra-ent manifestations

De visbestanden in Vlaanderen anno 1840-1950: een historische schets van de referentietoestand van onze waterlopen aan de hand van de visstand, ingevoerd in een databank en vergeleken met de actuele toestand

This study is a compilation of ‘historical’ fish stock references in Flanders (Belgium). It is part of an extended report to establish and describe the reference condition of Flandrian watercourses. To accomplish the survey for historical fish data, several sources were used: archaeological investigations of remains from settlements, documents from abbeys and reports on toll levies and very early fisheries reports dating from before 1840. Later, some scientific reports became available and also fisheries statistics became more reliable. The examination of museum collections gave additional data. In some cases, inquiries collecting verbal references can be a possible source of information. The most important source of information was the Belgian fisheries journal Pêche et Pisciculture: the volumes from the period 1890 to 1943 contained about 10 000 pages with numerous fish data. After analysis of the data a reference period was set on 1840-1950, although it is obvious that already then, several anthropogenic influences had put a lot of pressure on aquatic habitats. This was reflected in (1) a general decline in migrating species, (2) a decline in the number of sensitive reophylic species and (3) an increase in occurrence of non-indigenous species due to introductions. It was possible to calculate an Index of Biotic Integrity, using the historical fish data, to give an indication about the ecological quality of our watercourses in that period. Compared to actual data, the general tendency was a decrease in ecological quality from good to critical in many water courses. This decrease in IBI during the last century is caused by an increase of non-indigenous species, an increase in the number of tolerant species and a decrease in the relative abundance of predator species. It is obvious that knowledge of the historical status of fish stocks is essential to set up management plans and targets on national, regional or catchment level. The Water Framework Directive obliges member states to evaluate ecological quality of watercourses by quantifying the actual status of the biological element ‘fish’ in comparison to the reference condition

¹H NMR study of inclusion compounds of phenylurea derivatives in &beta

Proton nuclear magnetic resonance spectroscopy (1H NMR), which has become an important tool for the study “in situ” of β-cyclodextrin (β-CD) complexes, was used to study and structurally characterize the inclusion complexes formed between β-CD and isoproturon, fenuron, monuron and diuron. The high variation of the chemical shifts from the proton located inside the cavity (H-3, H-5 and H-6) coupled with the non variation of the one located outer sphere of the β-CD (H-1, H-2 and H-4) provided clear evidence of the inclusion phenomena. Two-dimensional rotating frame Overhauser effect spectroscopy (ROESY) experiments were carried out to further support the proposed inclusion mode