Adiposity Associated Plasma Linoleic Acid is Related to Demographic, Metabolic Health and Haplotypes of FADS1/2 Genes in Irish Adults

Scope: This study examined to what extent plasma linoleic acid (LA) is modified by adiposity, and explored any association between plasma LA, demographics, dietary intakes, markers of metabolic health and haplotypes of the fatty acid desaturase (FADS) 1/2 genes. Methods and results: 820 participants with fasting blood samples from Irish National Adult Nutrition Survey were studied. Plasma fatty acids were determined using GC-MS. 15 SNPs of FADS 1/2 genes were genotyped. Plasma LA decreased while γ-linoleic acid and dihomo-γ-linoleic acid increased in overweight/obese participants (P ≤ 0.002). Participants in the highest quartile of plasma LA showed decreased plasma markers of de novo lipogenesis, insulin resistance and of inflammation (TNF-α, PAI-1) (P ≤ 0.005). Adiposity (waist circumference and body fat) was strongly inversely associated with plasma LA accounting for 11.8% of variance observed, which was followed by FADS1/2 haplotypes (3.9 %), quantity and quality of carbohydrate intakes (3.8 %), dietary PUFA intakes (3.7 %), systolic blood pressure (3.6 %) and age (3.2 %). Conclusion: Plasma LA was inversely associated with adiposity, followed by haplotypes of FADS1/2 genes, carbohydrate intakes and dietary PUFA intakes. The association observed between plasma LA and adiposity may be linked to decreased de novo lipogenesis, insulin resistance and inflammation

Human Mutation within Per-Arnt-Sim (PAS) Domain-containing Protein Kinase (PASK) Causes Basal Insulin Hypersecretion*

Background: The glucose sensor PAS kinase (PASK) plays a fundamental role in pancreatic islet physiology

Architecture des aquifères rocheux et niveaux de circulation d’eau dans l’observatoire de la zone critique du Strengbach (France)

International audienceWe present an integrated petrological, petrophysical, and hydrogeological study of the critical zone (CZ) developed in the Hercynian granitic basement of the Strengbach watershed (Vosges Massif, France) to characterize its deep architecture and water circulation levels. For this purpose, six boreholes (50–120 m depth), from which three are cored, and three piezometers (10–15 m depth) were drilled to define the vertical extension and lateral variability of the main CZ horizons.The Strengbach watershed is composed of a topsoil horizon of limited vertical extension (0.8–1.2 m), a mobile saprolite level, and an in-place fractured bedrock. The latter is subdivided into a few meters thick saprock horizon, defined by open sub-horizontal fractures and a deeper fractured bedrock horizon with steeply dipping fractures (50°). In the north-facing slope, the vertical extension of the mobile saprolite horizon increases from 1–2 m at the top of the slope to 9 m downstream, close to the valley bottom. In contrast, the south-facing and more easterly slope shows a mobile saprolite horizon with limited vertical extension (2–3 m thick). Such a difference is associated with the existence of a knickpoint in the river bed, separating a downstream zone marked by currently active erosion from an upstream one, less prone to erosion, with preserved reliefs formed around 20 ka ago.The water circulation scheme within the Strengbach watershed involves two different systems: a subsurface circulation within the shallow aquifer, corresponding to the mobile saprolite horizon and the saprock, and a deeper circulation in the fractured bedrock. The water circulation in the fractured bedrock is controlled by fractures of regional orientations, linked to the Vosges massif and the Rhine Graben Tertiary tectonics, and partly to reactivated Hercynian fracture zones. The unaltered bedrock was not reached by any of the three cores. These results from the Strengbach CZ demonstrate the importance of integrating geological history of the watershed, either the long-term geological bedrock evolution or the Quaternary erosion patterns, to better understand and model the CZ hydrological functioning at the watershed scale.Nous présentons ici une étude pétrologique, pétrophysique et hydrogéologique intégrée de la zone critique (ZC) développée dans le socle granitique hercynien du bassin versant du Strengbach (Massif des Vosges, France), afin de caractériser son architecture profonde et ses niveaux de circulation d’eau. Dans ce but, six forages (50–120 m de profondeur), dont trois carottés, et trois piézomètres (10–15 m de profondeur) ont été réalisés, afin de définir l’extension verticale et la variabilité latérale des principaux horizons de la ZC.Le bassin versant du Strengbach est composé d’un horizon de sol d’extension verticale limitée (0,8–1,2 m), d’un niveau de saprolite mobile, et d’une roche mère en place fracturée. Cette dernière se subdivise en un horizon de « saprock » de quelques mètres d’épaisseur, défini par des fractures ouvertes subhorizontales, et un horizon plus profond de roche mère fracturée par des fractures à fort pendage (50 °). Dans le versant orienté au nord, l’extension verticale de l’horizon de saprolite mobile passe de 1–2 m au sommet du versant à 9 m en aval, au voisinage du vallon. En revanche, le versant orienté au sud et plus à l’est présente un horizon de saprolite mobile d’extension verticale limitée (2–3 m d’épaisseur). Une telle différence est probablement liée à l’existence d’un point d’inflexion dans le lit de la rivière (« Knickpoint »), séparant une zone aval marquée par une érosion actuellement active d’une zone amont, moins sujette à l’érosion, comprenant des reliefs préservés formés il y a environ 20 ka.Le schéma de circulation d’eau dans le bassin versant du Strengbach implique deux systèmes différents de circulation : une circulation dans l’aquifère de surface, constitué de l’horizon de saprolite mobile et du niveau de « saprock », et une circulation plus profonde dans la roche mère fracturée. La circulation d’eau dans la roche mère fracturée est contrôlée par des fractures d’orientations régionales, liées à la tectonique tertiaire du massif des Vosges et du fossé rhénan, ayant réactivé en partie au moins des fractures hercyniennes. Aucune des trois carottes n’a atteint le substrat rocheux non altéré. Ces résultats obtenus sur le bassin versant du Strengbach démontrent l’importance d’intégrer l’histoire géologique du bassin versant, qu’il s’agisse de l’évolution géologique long-terme de son substratum ou des processus d’érosion Quaternaire qui l’ont affecté, pour mieux comprendre et modéliser le fonctionnement hydrologique de la ZC à l’échelle du bassin versant

Glial Fibrillary Acidic Protein Autoimmunity A French Cohort Study

International audienceBackground and Objectives To report the clinical, biological, and imaging features and clinical course of a French cohort of patients with glial fibrillary acidic protein (GFAP) autoantibodies. Methods We retrospectively included all patients who tested positive for GFAP antibodies in the CSF by immunohistochemistry and confirmed by cell-based assay using cells expressing human GFAP alpha since 2017 from 2 French referral centers. Results We identified 46 patients with GFAP antibodies. Median age at onset was 43 years, and 65% were men. Infectious prodromal symptoms were found in 82%. Other autoimmune diseases were found in 22% of patients, and coexisting neural autoantibodies in 11%. Tumors were present in 24%, and T-cell dysfunction in 23%. The most frequent presentation was subacute meningoencephalitis (85%), with cerebellar dysfunction in 57% of cases. Other clinical presentations included myelitis (30%) and visual (35%) and peripheral nervous system involvement (24%). MRI showed perivascular radial enhancement in 32%, periventricular T2 hyperintensity in 41%, brainstem involvement in 31%, leptomeningeal enhancement in 26%, and reversible splenial lesions in 4 cases. A total of 33 of 40 patients had a monophasic course, associated with a good outcome at last follow-up (Rankin Score <= 2: 89%), despite a severe clinical presentation. Adult and pediatric features are similar. Thirty-two patients were treated with immunotherapy. A total of 11/22 patients showed negative conversion of GFAP antibodies. Discussion GFAP autoimmunity is mainly associated with acute/subacute meningoencephalomyelitis with prodromal symptoms, for which tumors and T-cell dysfunction are frequent triggers. The majority of patients followed a monophasic course with a good outcome

Penetrance estimation of Alzheimer disease in SORL1 loss-of-function variant carriers using a family-based strategy and stratification by APOE genotypes

International audienceAbstract Background Alzheimer disease (AD) is a common complex disorder with a high genetic component. Loss-of-function (LoF) SORL1 variants are one of the strongest AD genetic risk factors. Estimating their age-related penetrance is essential before putative use for genetic counseling or preventive trials. However, relative rarity and co-occurrence with the main AD risk factor, APOE -ε4, make such estimations difficult. Methods We proposed to estimate the age-related penetrance of SORL1 -LoF variants through a survival framework by estimating the conditional instantaneous risk combining (i) a baseline for non-carriers of SORL1- LoF variants, stratified by APOE-ε4 , derived from the Rotterdam study ( N = 12,255), and (ii) an age-dependent proportional hazard effect for SORL1- LoF variants estimated from 27 extended pedigrees (including 307 relatives ≥ 40 years old, 45 of them having genotyping information) recruited from the French reference center for young Alzheimer patients. We embedded this model into an expectation-maximization algorithm to accommodate for missing genotypes. To correct for ascertainment bias, proband phenotypes were omitted. Then, we assessed if our penetrance curves were concordant with age distributions of APOE -ε4-stratified SORL1- LoF variant carriers detected among sequencing data of 13,007 cases and 10,182 controls from European and American case-control study consortia. Results SORL1- LoF variants penetrance curves reached 100% (95% confidence interval [99–100%]) by age 70 among APOE -ε4ε4 carriers only, compared with 56% [40–72%] and 37% [26–51%] in ε4 heterozygous carriers and ε4 non-carriers, respectively. These estimates were fully consistent with observed age distributions of SORL1- LoF variant carriers in case-control study data. Conclusions We conclude that SORL1- LoF variants should be interpreted in light of APOE genotypes for future clinical applications