Evaluation of presumably disease causing SCN1A variants in a cohort of common epilepsy syndromes

Objective: The SCN1A gene, coding for the voltage-gated Na+ channel alpha subunit NaV1.1, is the clinically most relevant epilepsy gene. With the advent of high-throughput next-generation sequencing, clinical laboratories are generating an ever-increasing catalogue of SCN1A variants. Variants are more likely to be classified as pathogenic if they have already been identified previously in a patient with epilepsy. Here, we critically re-evaluate the pathogenicity of this class of variants in a cohort of patients with common epilepsy syndromes and subsequently ask whether a significant fraction of benign variants have been misclassified as pathogenic. Methods: We screened a discovery cohort of 448 patients with a broad range of common genetic epilepsies and 734 controls for previously reported SCN1A mutations that were assumed to be disease causing. We re-evaluated the evidence for pathogenicity of the identified variants using in silico predictions, segregation, original reports, available functional data and assessment of allele frequencies in healthy individuals as well as in a follow up cohort of 777 patients. Results and Interpretation: We identified 8 known missense mutations, previously reported as path

The handbook for standardised field and laboratory measurements in terrestrial climate-change experiments and observational studies

Climate change is a worldwide threat to biodiversity and ecosystem structure, functioning, and services. To understand the underlying drivers and mechanisms, and to predict the consequences for nature and people, we urgently need better understanding of the direction and magnitude of climate‐change impacts across the soil–plant–atmosphere continuum. An increasing number of climate‐change studies is creating new opportunities for meaningful and high‐quality generalisations and improved process understanding. However, significant challenges exist related to data availability and/or compatibility across studies, compromising opportunities for data re‐use, synthesis, and upscaling. Many of these challenges relate to a lack of an established “best practice” for measuring key impacts and responses. This restrains our current understanding of complex processes and mechanisms in terrestrial ecosystems related to climate change

Analysis of shared heritability in common disorders of the brain

Paroxysmal Cerebral Disorder

Theoretical study on the role of surface basicity and Lewis acidity on the etherification of glycerol over alkaline earth metal oxides

Alkaline earth metal oxides (MO) are catalytically active in the etherification of glycerol. Density Functional Theory (DFT) calculations have been used to examine the reactivity of glycerol with MO surfaces with M=Mg, Ca, Sr or Ba. More specifically, the optimum glycerol adsorption mode and the strength of glycerol interaction with regular MO (001) surfaces and a stepped CaO surface have been investigated and involves the interaction with acid-base surface sites. The basicity of lattice oxygen atoms is correlated with the adsorption energy: BaO (-3.02 eV) > SrO (-2.85 eV) > CaO (-2.05 eV) > MgO (-1.35 eV). The interactions have an exothermic character, that is, the more basic the alkaline earth metal oxide, the more exothermic is the adsorption process and the higher the dissociation extent. Thus, the dissociation of glycerol increases in the order: MgO (not dissociated) <CaO (partially dissociated <SrO (partially dissociated) <BaO (completely dissociated). The presence of defects is found to play a key role in the mechanism: glycerol interaction with a stepped CaO surface presents the highest adsorption energy (-3.78 eV), and the molecule is found to dissociate at the step. The calculated structural parameters are found to be in good agreement with experimental data on catalyst reactivity. Moreover, the earlier postulated reaction mechanism, which also involves the additional involvement of Lewis acid sites proved to be feasible for CaO and SrO regular surfaces, and for the stepped CaO surface. It was found that for these oxides one of the most favored adsorption modes involves a non-dissociative adsorption of one hydroxyl group of glycerol, which as a result becomes a better leaving group. Therefore, theoretical evidence was found for the possible direct involvement of Lewis acid sites in the catalytic etherification of bio-derived alcohols, such as glycerol, as it is anticipated that these observations can be extended to sugar alcohols as well

Glycerol etherification over highly active CaO-based materials: new mechanistic aspects and related colloidal particle formation

Glycerol is an attractive renewable building block for the synthesis of di- and triglycerols, which have numerous applications in the cosmetic and pharmaceutical industries. In this work, the selective etherification of glycerol to di- and triglycerol was studied in the presence of alkaline earth metal oxides and the data are compared with those obtained with Na2CO3 as a homogeneous catalyst. It was found that glycerol conversion increased with increasing catalyst basicity; that is, the conversion increases in the order: MgO90 % at 60 % conversion) are obtained over CaO, SrO, and BaO. For these catalysts no substantial acrolein formation was observed. Furthermore, at the start of the reaction mainly linear diglycerol was produced, whereas at higher conversion degrees branched diglycerol started to form. In another series of experiments different types of CaO materials were prepared. It was found that these CaO-based materials not only differed in their surface area and number of basic sites, but also in their Lewis acid strength. Within this series the CaO material possessing the strongest Lewis acid sites had the highest catalytic activity, comparable to that of BaO, pointing towards the important role of Lewis acidity for this etherification reaction. Based on these observations a plausible alternative reaction scheme for glycerol etherification is presented, which considers the facilitation of the hydroxyl leaving process. Finally, the stability of the catalytic solids under study was investigated and it was found that colloidal CaO particles of about 50-100 nm can be spontaneously generated during reaction. Catalytic testing of these CaO colloids, after isolation from the reaction medium, revealed a very high etherification activity. Understanding the nature of these Ca-based colloids opens new opportunities for investigating supported colloidal particle catalysts to take advantage of both their hetero- and homogeneous nature

Synthesis of long alkyl chain ethers through direct etherification of biomass-based alcohols with 1-octene over heterogeneous acid catalysts

Heterogeneous etherification of various biomass-based alcohols with 1-octene was investigated as a direct route for the synthesis of long alkyl chain ethers. Several acid catalyst materials including Amberlyst resins and various zeolites were screened as etherification catalysts in a solventless system. It was found that H-Beta zeolites are the most selective catalysts for the etherification of biomass-based alcohols with 1-octene to the corresponding mono-ethers. With H-Beta the conversion of neat glycerol was around 15–20% and increased to 54–89% for glycols such as ethylene glycol and 1,2-propylene glycol, with high selectivities to mono- and di-octyl ethers of 85–97%. Other linear alkenes like 1-dodecene and 1-hexadecene were successfully employed in the direct etherification of glycols as well. Crude glycerol was also etherified, albeit with low conversions. The influence of several reaction parameters on the etherification activity of H-Beta has been investigated together with catalyst recovery and re-use