Clinical variants paired with phenotype: A rich resource for brain gene curation.

PURPOSE: Clinically ascertained variants are under-utilized in neurodevelopmental disorder research. We established the Brain Gene Registry (BGR) to coregister clinically identified variants in putative brain genes with participant phenotypes. Here, we report 179 genetic variants in the first 179 BGR registrants and analyze the proportion that were novel to ClinVar at the time of entry and those that were absent in other disease databases. METHODS: From 10 academically affiliated institutions, 179 individuals with 179 variants were enrolled into the BGR. Variants were cross-referenced for previous presence in ClinVar and for presence in 6 other genetic databases. RESULTS: Of 179 variants in 76 genes, 76 (42.5%) were novel to ClinVar, and 62 (34.6%) were absent from all databases analyzed. Of the 103 variants present in ClinVar, 37 (35.9%) were uncertain (ClinVar aggregate classification of variant of uncertain significance or conflicting classifications). For 5 variants, the aggregate ClinVar classification was inconsistent with the interpretation from the BGR site-provided classification. CONCLUSION: A significant proportion of clinical variants that are novel or uncertain are not shared, limiting the evidence base for new gene-disease relationships. Registration of paired clinical genetic test results with phenotype has the potential to advance knowledge of the relationships between genes and neurodevelopmental disorders

Study of the selective extraction by innovative processes of peptides from the enzymatic proteolysis of bovine haemoglobin

Trois procédés innovants ont permis d’extraire sélectivement des peptides actifs d’un hydrolysat complexe issu de la protéolyse pepsique de l’hémoglobine bovine. Un premier procédé d’extraction biphasique assistée par des alkyl-sulfonates a permis de modifier l’affinité des peptides pour la phase organique par la formation de paires d’ions. Ces études des conditions d’extraction de peptides opioïdes hydrophobes ont permis la mise en œuvre d’un système d’extraction dans l’octan-1-ol supporté par un contacteur à membrane. Dans un deuxième temps, un procédé de moussage-drainage fut développé sur les propriétés tensioactives des peptides et a permis de fractionner la population peptidique pour isoler une fraction aux propriétés antibactériennes. L’optimisation par plans d’expériences a mis en avant l’influence de quatre paramètres majeurs (concentrations en hydrolysat et en sel, pH des solutions d’hydrolysat et de drainage) et a permis de multiplier par 3,4 l’enrichissement de cette fraction dans la solution récoltée. Enfin un procédé récemment développé, l’électrodialyse associée à des membranes d’ultrafiltration ayant pour seule force motrice la différence de potentiel électrique, a permis d’isoler une fraction peptidique cationique. L’étude du comportement en encrassement a révélé l’existence de phénomènes de répulsion de charges empêchant la récolte d’une fraction peptidique anionique et la formation d’agrégats hème-peptides colmatant de manière partiellement réversible les membranes d’ultrafiltration.Three innovative processes allowed to extract selectively active peptides from a complex hydrolysate from the pepsic proteolysis of bovine haemoglobin. A first process of biphasic extraction assisted by alkyl-sulfonates allowed to modify the affinity of peptides for the organic phase by the formation of ion-pairs. These studies of conditions of extraction of opioid hydrophobe peptides allowed the implementation of a system of extraction in octan-1-ol supported by a membrane contactor. Secondly, a process of bubbling-draining was developed based on the surface tension properties of the peptides and allowed to split the peptidic population to isolate a fraction showing antibacterial properties. The optimization by experimental design advanced the influence of four major parameters (concentrations of hydrolysate and KCl, pH of solutions of hydrolysate and drainage) and allowed to multiply by 3,4 the enrichment of this fraction in the collected solution. Finally a process recently developed, the electrodialysis associated with ultrafiltration membranes having for only driving strength the difference of electric potential, allowed to isolate a cationic peptidic fraction. The study of the behavior in fouling revealed the existence of phenomena of charge repulsion preventing the isolation of a anionic peptidic fraction and the formation of aggregates haem-peptides fouling in a partially reversible way the ultrafiltration membranes

[[The]] retrotransposon Ty1 extends chronological lifespan in Saccharomyces paradoxus by influencing cellular responses to stress

May 2015School of ScienceAdvancing age of the global population is resulting in an increase in the accumulation of age-related pathologies. Many potential molecular and cellular causes of aging are still being debated. Endogenous retroelements are a class of mobile DNA elements that have coexisted in the genomes of virtually every eukaryotic organism for much of evolution. Recent work indicates that retrotransposons are active in advanced age but their impact on aging has not been explored in detail. Evidence is accumulating to suggest that retrotransposon-mediated events are a potential source of genomic change that can influence aging. In this study I took advantage of a unique yeast model system to characterize aging in cells with or without Ty1 retroelements. I identify here a novel role of retroelements in extending yeast chronological lifespan in certain media conditions, rather than observing an anticipated pro-aging effect. This effect was correlated with changes in factors known to influence aging such as mitochondrial function, reactive oxygen species, and sensitivity to a chemical inhibitor of nutrient sensing pathways. These results demonstrate that the presence of these retroelements have unforeseen direct or indirect roles in influencing cellular processes relevant to lifespan. The ability of retrotransposons to regulate cellular functions has not been well investigated, in contrast to the ability of cellular pathways to regulate retrotransposons. The work here broadens our perspective on the role retrotransposons have in host cells to influence certain aspects of eukaryotic aging.Ph

LE SYNDROME D'ALCOOLISATION FOETALE

LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Étude de l'extraction sélective par des procédés innovants de peptides issus de la protéolyse enzymatique de l'hémoglobine bovine

Trois procédés innovants ont permis d extraire sélectivement des peptides actifs d un hydrolysat complexe issu de la protéolyse pepsique de l hémoglobine bovine. Un premier procédé d extraction biphasique assistée par des alkyl-sulfonates a permis de modifier l affinité des peptides pour la phase organique par la formation de paires d ions. Ces études des conditions d extraction de peptides opioïdes hydrophobes ont permis la mise en œuvre d un système d extraction dans l octan-1-ol supporté par un contacteur à membrane. Dans un deuxième temps, un procédé de moussage-drainage fut développé sur les propriétés tensioactives des peptides et a permis de fractionner la population peptidique pour isoler une fraction aux propriétés antibactériennes. L optimisation par plans d expériences a mis en avant l influence de quatre paramètres majeurs (concentrations en hydrolysat et en sel, pH des solutions d hydrolysat et de drainage) et a permis de multiplier par 3,4 l enrichissement de cette fraction dans la solution récoltée. Enfin un procédé récemment développé, l électrodialyse associée à des membranes d ultrafiltration ayant pour seule force motrice la différence de potentiel électrique, a permis d isoler une fraction peptidique cationique. L étude du comportement en encrassement a révélé l existence de phénomènes de répulsion de charges empêchant la récolte d une fraction peptidique anionique et la formation d agrégats hème-peptides colmatant de manière partiellement réversible les membranes d ultrafiltration.Three innovative processes allowed to extract selectively active peptides from a complex hydrolysate from the pepsic proteolysis of bovine haemoglobin. A first process of biphasic extraction assisted by alkyl-sulfonates allowed to modify the affinity of peptides for the organic phase by the formation of ion-pairs. These studies of conditions of extraction of opioid hydrophobe peptides allowed the implementation of a system of extraction in octan-1-ol supported by a membrane contactor. Secondly, a process of bubbling-draining was developed based on the surface tension properties of the peptides and allowed to split the peptidic population to isolate a fraction showing antibacterial properties. The optimization by experimental design advanced the influence of four major parameters (concentrations of hydrolysate and KCl, pH of solutions of hydrolysate and drainage) and allowed to multiply by 3,4 the enrichment of this fraction in the collected solution. Finally a process recently developed, the electrodialysis associated with ultrafiltration membranes having for only driving strength the difference of electric potential, allowed to isolate a cationic peptidic fraction. The study of the behavior in fouling revealed the existence of phenomena of charge repulsion preventing the isolation of a anionic peptidic fraction and the formation of aggregates haem-peptides fouling in a partially reversible way the ultrafiltration membranes.LILLE1-Bib. Electronique (590099901) / SudocSudocFranceF

Continuous preparation of two opioïd peptides and recycling of organic solvent using liquid/liquid extraction coupled with aluminium oxide column during haemoglobin hydrolysis by immobilized pepsin

International audiencePreviously, success in producing and extracting continuously LVV-heamorphin-7 and VV-haemorphin-7 in an aqueous/butan-2-ol-octan-1-ol biphasic medium in the course of hydrolysis of bovine haemoglobin by immobilized pepsin was achieved. In this paper, the coupling of the continuous hydrolysis of haemoglobin by pepsin immobilized on a duolite with concomitant extraction of the two haemorphins and haem by a butan-2-ol-octan-1-ol mixture, their adsorption on an aluminium oxide column and the recycling of the solvent mixture in the reactor are described. A steady-state for haemorphin concentrations in the regenerated organic phase at the outlet of the continuous-stirred-tank-reactor (CSTR) was achieved and maintained for more than 10 bed volumes. Finally, the two haemorphins were selectively eluted from the aluminium oxide column tank to a volatile ethanolamine solution.</div

Advancement of foam separation of bioactive peptides using an aeration column with a bubbling-draining method

International audiencePeptidic hydrolysates with different degrees of hydrolysis (3, 15 and 23%) has been obtained by hydrolysis of bovine haemoglobin by pepsin. RP-HPLC analysis of these hydrolysates coupled with mass spectroscopy has given information about the retention time and the peptidic size distribution. Pendant-drop tensiometry of aqueous-buffer solutions versus concentration points out differences in the curves superficial tension versus concentration between starting haemoglobin and hydrolysates. The weight percentage of hydrolysates in the bulk C max B for which stable foam can be obtained has been determined. Foam fractionation was studied by a bubbling-draining method. Collected top foam was analyzed by RP-HPLC and compared to the initial hydrolysate. No stable foam has been obtained with hydrolysate (DH = 23%) and no interesting fractionation can be obtained with hydrolysate (DH = 15%). However, a peptidic fraction (3500-7000 Da), having an antimicrobial activity, with a 5% extraction yield can be separated from hydrolysate (DH = 3%), using a forced draining volume of 100 or 150 mL.</div