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Abstract The recent emergence of chronic wasting disease (CWD) in Europe has become a new public health risk for monitoring of wild and farmed cervids. This disease, due to prions, has proliferated in North America in a contagious manner. In several mammalian species, polymorphisms in the prion protein gene (PRNP) play a crucial role in the susceptibility to prions and their spread. To obtain a reliable picture of the distribution of PRNP polymorphisms in the two most common cervid species in France, we sequenced the open reading frame (ORF) of this gene in 2114 animals, 1116 roe deer (Capreolus capreolus) and 998 red deer (Cervus elaphus). Selection criteria such as historical origin, spatial distribution and sex ratio have been integrated to establish this sample collection. Except for one heterozygous animal with a non-synonymous mutation at codon 37 (G37A), all the 1116 French roe deer were monomorphic. Red deer showed greater variation with two non-synonymous substitutions (T98A; Q226E), three synonymous substitutions (codons 21, 78 and 136) and a new 24pb deletion (Δ69-77). We found significant regional variations between French regions in the frequency of the identified substitutions. After cloning of the PRNP ORF from animals presenting multiple non-synonymous polymorphisms, we identified six haplotypes and obtained a total of twelve genotypes. As in other European countries, we highlighted the apparent homogeneity of PRNP in the French roe deer and the existence of a greater diversity in the red deer. These results were in line with European phylogeographic studies on these two species.

Abstract Astrocytes control brain activity via both metabolic processes and gliotransmission, but the physiological links between these functions are scantly known. Here we show that endogenous activation of astrocyte type-1 cannabinoid (CB1) receptors determines a shift of glycolysis towards the lactate-dependent production of d-serine, thereby gating synaptic and cognitive functions in male mice. Mutant mice lacking the CB1 receptor gene in astrocytes (GFAP-CB1-KO) are impaired in novel object recognition (NOR) memory. This phenotype is rescued by the gliotransmitter d-serine, by its precursor l-serine, and also by lactate and 3,5-DHBA, an agonist of the lactate receptor HCAR1. Such lactate-dependent effect is abolished when the astrocyte-specific phosphorylated-pathway (PP), which diverts glycolysis towards l-serine synthesis, is blocked. Consistently, lactate and 3,5-DHBA promoted the co-agonist binding site occupancy of CA1 post-synaptic NMDA receptors in hippocampal slices in a PP-dependent manner. Thus, a tight cross-talk between astrocytic energy metabolism and gliotransmission determines synaptic and cognitive processes.

Abstract Neuronal activity undergoes significant changes during vigilance states, accompanied by an accommodation of energy demands. While the astrocyte-neuron lactate shuttle has shown that lactate is the primary energy substrate for sustaining neuronal activity in multiple brain regions, its role in regulating sleep/wake architecture is not fully understood. Here we investigated the involvement of astrocytic lactate supply in maintaining consolidated wakefulness by downregulating, in a cell-specific manner, the expression of monocarboxylate transporters (MCTs) in the lateral hypothalamus of transgenic mice. Our results demonstrate that reduced expression of MCT4 in astrocytes disrupts lactate supply to wake-promoting orexin neurons, impairing wakefulness stability. Additionally, we show that MCT2-mediated lactate uptake is necessary for maintaining tonic firing of orexin neurons and stabilizing wakefulness. Our findings provide both in vivo and in vitro evidence supporting the role of astrocyte-to-orexinergic neuron lactate shuttle in regulating proper sleep/wake stability.

L’apprentissage en ligne dans des formations asynchrones est une composante essentielle de l’apprentissage tout au long de la vie. Toutefois, les personnes aînées en sont l’un des groupes les plus exclus. Il importe de les considérer, car plus tôt que tard, elles pourraient être confrontées à la nécessité de suivre ce type de formation. Pensons aux travailleurs expérimentés dans l’obligation de suivre une formation asynchrone déployée par leurs ordres professionnels pour continuer à pratiquer. Le X s’est associé à l’entreprise X, spécialisée en solutions éducatives en ligne, pour adapter une formation asynchrone conçue pour des travailleurs pour la rendre accessible à des personnes aînées. L’adaptation de la formation asynchrone a été décrite dans un canevas de formation qui synthétise les principes de conception à considérer pour le développement d’interfaces conviviales en e-learning pour les personnes aînées. Cet article décrit la recherche-action qui a permis son développement avec la participation de neuf personnes du Québec âgées de 71 à 83 ans. L’utilisation de deux cadres conceptuels, la conception centrée sur l’utilisateur et la conception d’interfaces utilisateurs pour une population vieillissante, ont été utilisés pour soutenir l’adaptation de la formation asynchrone et développer le canevas.

Wood has a lower carbon footprint compared to many other materials used in construction. However, its hygroscopic nature poses significant challenges, including dimensional fluctuations in response to humidity shifts. Here we investigate a new treatment method mitigating swelling and shrinkage using dairy by-product named whey ultrafiltration permeate (mainly composed of lactose) and citric acid. Trembling aspen and black spruce samples were impregnated with ultrafiltration permeate and citric acid. Infrared and Raman spectroscopy were used to evaluate the esterification reaction and the location of the impregnates. We found increased ester bonds in the cell walls and the middle lamella (leaving the lumens empty), explaining the improved wood stability. Trembling aspen was more receptive to the treatment than black spruce, as shown by a higher weight gain (39 % vs. 13 %) and anti-swelling efficiency (54 % vs. 37 %). No leaching was observed during characterization of the treated wood. The modulus of elasticity and rupture, and the Brinell hardness were only slightly affected for both wood species. Upon combustion, esterified wood samples degraded at a lower temperature, but the stability of the residues was increased. This study highlights a promising use of ultrafiltration permeate in wood esterification.

Abstract Numerous drivers such as farming practices, erosion, land-use change, and soil biogeochemical background, determine the global spatial distribution of phosphorus (P) in agricultural soils. Here, we revised an approach published earlier (called here GPASOIL-v0), in which several global datasets describing these drivers were combined with a process model for soil P dynamics to reconstruct the past and current distribution of P in cropland and grassland soils. The objective of the present update, called GPASOIL-v1, is to incorporate recent advances in process understanding about soil inorganic P dynamics, in datasets to describe the different drivers, and in regional soil P measurements for benchmarking. We trace the impact of the update on the reconstructed soil P. After the update we estimate a global averaged inorganic labile P of 187 kgP ha−1 for cropland and 91 kgP ha−1 for grassland in 2018 for the top 0–0.3 m soil layer, but these values are sensitive to the mineralization rates chosen for the organic P pools. Uncertainty in the driver estimates lead to coefficients of variation of 0.22 and 0.54 for cropland and grassland, respectively. This work makes the methods for simulating the agricultural soil P maps more transparent and reproducible than previous estimates, and increases the confidence in the new estimates, while the evaluation against regional dataset still suggests rooms for further improvement.

In this study, we introduced a mathematical model mimicking as much as possible the evolutions and interactions between glioma and lactate in the brain, in order to test different therapies and administration protocols. We simulated both glioma cell density evolution and lactate concentration, and considered two therapies: chemotherapy and a treatment targeting lactate production. Three different protocols for administrating the therapies were tested. We compared the efficiency of the combined therapies, depending on the administration protocols and the dosage of the drugs, in order to evaluate the importance of controlling lactate production. Results show that the use of an agent to reduce lactate concentration permits one to significantly reduce the dose of the chemotherapeutic drug.

Objective: Ketone bodies (such as β-hydroxybutyrate or BHB) have been recently proposed as signals involved in brain regulation of energy homeostasis and obesity development. However, the precise role of ketone bodies sensing by the brain, and its impact on metabolic disorder development remains unclear. Nevertheless, partial deletion of the ubiquitous ketone bodies transporter MCT1 in mice (HE mice) results in diet-induced obesity resistance, while there is no alteration under normal chow diet. These results suggest that ketone bodies produced during the high fat diet would be important signals involved in obesity onset. Methods: In the present study we used a specific BHB infusion of the hypothalamus and analyzed the energy homeostasis of WT or HE mice fed a normal chow diet. Results: Our results indicate that high BHB levels sensed by the hypothalamus disrupt the brain regulation of energy homeostasis. This brain control dysregulation leads to peripheral alterations of energy expenditure mechanisms. Conclusions: Altogether, the changes induced by high ketone bodies levels sensed by the brain increase the risk of obesity onset in mice.

Summary: Background: GAA-FGF14 disease/spinocerebellar ataxia 27B is a recently described neurodegenerative disease caused by (GAA)≥250 expansions in the fibroblast growth factor 14 (FGF14) gene, but its phenotypic spectrum, pathogenic threshold, and evidence-based treatability remain to be established. We report on the frequency of FGF14 (GAA)≥250 and (GAA)200-249 expansions in a large cohort of patients with idiopathic downbeat nystagmus (DBN) and their response to 4-aminopyridine. Methods: Retrospective cohort study of 170 patients with idiopathic DBN, comprising in-depth phenotyping and assessment of 4-aminopyridine treatment response, including re-analysis of placebo-controlled video-oculography treatment response data from a previous randomised double-blind 4-aminopyridine trial. Findings: Frequency of FGF14 (GAA)≥250 expansions was 48% (82/170) in patients with idiopathic DBN. Additional cerebellar ocular motor signs were observed in 100% (82/82) and cerebellar ataxia in 43% (35/82) of patients carrying an FGF14 (GAA)≥250 expansion. FGF14 (GAA)200-249 alleles were enriched in patients with DBN (12%; 20/170) compared to controls (0.87%; 19/2191; OR, 15.20; 95% CI, 7.52–30.80; p

Summary: Background: An intronic GAA repeat expansion in FGF14 was recently identified as a cause of GAA-FGF14 ataxia. We aimed to characterise the frequency and phenotypic profile of GAA-FGF14 ataxia in a large Chinese ataxia cohort. Methods: A total of 1216 patients that included 399 typical late-onset cerebellar ataxia (LOCA), 290 early-onset cerebellar ataxia (EOCA), and 527 multiple system atrophy with predominant cerebellar ataxia (MSA-c) were enrolled. Long-range and repeat-primed PCR were performed to screen for GAA expansions in FGF14. Targeted long-read and whole-genome sequencing were performed to determine repeat size and sequence configuration. A multi-modal study including clinical assessment, MRI, and neurofilament light chain was conducted for disease assessment. Findings: 17 GAA-FGF14 positive patients with a (GAA)≥250 expansion (12 patients with a GAA-pure expansion, five patients with a (GAA)≥250-[(GAA)n (GCA)m]z expansion) and two possible patients with biallelic (GAA)202/222 alleles were identified. The clinical phenotypes of the 19 positive and possible positive cases covered LOCA phenotype, EOCA phenotype and MSA-c phenotype. Five of six patients with EOCA phenotype were found to have another genetic disorder. The NfL levels of patients with EOCA and MSA-c phenotypes were significantly higher than patients with LOCA phenotype and age-matched controls (p

ABSTRACT: Adequate prediction of postruminal outflow of protein fractions is the starting point for the determination of metabolizable protein supply in dairy cows. The objective of this meta-analysis was to compare the performance of 3 dairy feed evaluation systems (National Research Council [NRC], Cornell Net Protein and Carbohydrate System [CNCPS], and National Academies of Sciences, Engineering and Medicine [NASEM]) to predict outflows (g/d) of nonammonia nitrogren (NAN), microbial N (MiN), and nonammonia nonmicrobial N (NANMN). Predictions of rumen degradabilities (% of nutrient) of protein (RDP), NDF, and starch were also evaluated. The data set included 1,294 treatment means from 312 digesta flow studies. The 3 feed evaluation systems were compared using the concordance correlation coefficient (CCC), the ratio of root mean square prediction error (RMSPE) on standard deviation of observed values (RSR), and the slope between observed and predicted values. Mean and linear biases were deemed biologically relevant and are discussed if higher than a threshold of 5% of the mean of observed values. The comparisons were done on observed values adjusted or not for the study effect; the adjustment had a small effect on the mean bias but the linear bias reflected a response to a dietary change rather than absolute predictions. For the absolute predictions of NAN and MiN, CNCPS had the best-fit statistics (8% greater CCC; 6% lower RMSPE) without any bias; NRC and NASEM underpredicted NAN and MiN, and NASEM had an additional linear bias indicating that the underprediction of MiN increased at increased predictions. For NANMN, fit statistics were similar among the 3 feed evaluation systems with no mean bias; however, the linear bias with NRC and CNCPS indicated underprediction at low predictions and overprediction at elevated predictions. On average, the CCC were smaller and RSR ratios were greater for MiN versus NAN indicating increased prediction errors for MiN. For NAN responses to a dietary change, CNCPS also had the best predictions, although the mean bias with NASEM was not biologically relevant and the 3 feed evaluation systems did not present a linear bias. However, CNCPS, but not the 2 other feed evaluation systems, presented a linear bias for MiN, with responses being overpredicted at increased predictions. For NANMN, responses were overpredicted at increased predictions for the 3 feed evaluation systems, but to a lesser extent with NASEM. The site of sampling had an effect on the mean bias of MiN and NANMN in the 3 feed evaluation systems. The mean bias of MiN was higher in omasal than duodenal studies in the 3 feed evaluation systems (from 55 to 61 g/d) and this mean bias was twice as large when 15N labeling was used as a microbial marker compared with purines. Such a difference was not observed for duodenal studies. The reasons underlying these systematic differences are not clear as the type of measurements used in the current meta-analysis does not allow to delineate if one site or one microbial marker is yielding the “true” postruminal N outflows. Rumen degradabilities of protein was underpredicted with CNCPS, and RDP responses to a dietary change was underpredicted by the 3 feed evaluation systems with increased RDP predictions. Rumen degradability of NDF was underpredicted and had poor fit statistics for NASEM compared with CNCPS. Fit statistics were similar between CNCPS and NASEM for rumen degradability of starch, but with an underprediction of the response with NASEM and absolute values being overpredicted with CNCPS. Multivariate regression analyses showed that diet characteristics were correlated with prediction errors of N outflows in each feed evaluation system. Globally, compared with NAN and NANMN, residuals of MiN were correlated with several moderators in the 3 feed evaluation systems reflecting the complexity to measure and model this outflow. In addition, residuals of NANMN were correlated positively with RDP suggesting an overestimation of this parameter. In conclusion, although progress is still to be made to improve equations predicting postruminal N outflows, the current feed evaluation systems provide sufficient precision and accuracy to predict postruminal outflows of N fractions.