Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.Objective: To identify the genetic variants associated with juvenile ALS.Design, Setting, and Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.Main Outcomes and Measures: De novo variants present only in the index case and not in unaffected family members.Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.Conclusions and Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.</p

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

Inhomogeneous distribution of fat enhances the perception of fat-related sensory attributes in gelled foods

This study investigated the effect of the spatial distribution of fat on the perception of fat-related sensory attributes using a model system that consisted of layered agar/gelatin gels containing oil-in-water (O/W) emulsion droplets dispersed in the gel matrix. Four layers of gel varying in the amount of emulsion droplets were combined to prepare samples with homogeneous and inhomogeneous distributions of fat (emulsion droplets). The composition of the gels was optimized to obtain samples with comparable mechanical properties. A significant enhancement of mouthfeel attributes such as spreadable and melting was observed in samples with inhomogeneous distributions of fat in a Quantitative Descriptive Analysis (QDA) panel. Inhomogeneous samples with large differences in fat content between layers were perceived more spreadable and melting than the sample in which fat was homogeneously distributed. Creaminess ratings tended to increase as the difference in fat content between layers increased in the inhomogeneous samples. Additionally, the position of the high-fat layers in the sample affected the perception of fat-related attributes. The sample with high-fat layers on the outside had the highest ratings for all mouthfeel and afterfeel attributes. The enhancement of fat-related attributes by an inhomogeneous distribution of fat depended on the overall fat content. The enhancement at 15 wt% fat was larger than that at 5 wt% fat. We suggest that the modulation of the spatial distribution of fat can be used to reduce the fat content of food products without causing undesirable changes in the sensory propertie

Inhomogeneous distribution of fat enhances the perception of fat-related sensory attributes in gelled foods

This study investigated the effect of the spatial distribution of fat on the perception of fat-related sensory attributes using a model system that consisted of layered agar/gelatin gels containing oil-in-water (O/W) emulsion droplets dispersed in the gel matrix. Four layers of gel varying in the amount of emulsion droplets were combined to prepare samples with homogeneous and inhomogeneous distributions of fat (emulsion droplets). The composition of the gels was optimized to obtain samples with comparable mechanical properties. A significant enhancement of mouthfeel attributes such as spreadable and melting was observed in samples with inhomogeneous distributions of fat in a Quantitative Descriptive Analysis (QDA) panel. Inhomogeneous samples with large differences in fat content between layers were perceived more spreadable and melting than the sample in which fat was homogeneously distributed. Creaminess ratings tended to increase as the difference in fat content between layers increased in the inhomogeneous samples. Additionally, the position of the high-fat layers in the sample affected the perception of fat-related attributes. The sample with high-fat layers on the outside had the highest ratings for all mouthfeel and afterfeel attributes. The enhancement of fat-related attributes by an inhomogeneous distribution of fat depended on the overall fat content. The enhancement at 15 wt% fat was larger than that at 5 wt% fat. We suggest that the modulation of the spatial distribution of fat can be used to reduce the fat content of food products without causing undesirable changes in the sensory propertie

Contrasting patterns of nucleotide diversity for four conifers of Alpine European forests

A candidate gene approach was used to identify levels of nucleotide diversity and to identify genes departing from neutral expectations in coniferous species of the Alpine European forest. Twelve samples were collected from four species that dominate montane and subalpine forests throughout Europe: Abies alba Mill, Larix decidua Mill, Pinus cembra L., and Pinus mugo Turra. A total of 800 genes, originally resequenced in Pinus taeda L., were resequenced across 12 independent trees for each of the four species. Genes were assigned to two categories, candidate and control, defined through homology-based searches to Arabidopsis. Estimates of nucleotide diversity per site varied greatly between polymorphic candidate genes (range: 0.0004–0.1295) and among species (range: 0.0024–0.0082), but were within the previously established ranges for conifers. Tests of neutrality using stringent significance thresholds, performed under the standard neutral model, revealed one to seven outlier loci for each species. Some of these outliers encode proteins that are involved with plant stress responses and form the basis for further evolutionary enquiries

Deadenylation of interferon-beta mRNA is mediated by both the AU-rich element in the 3'-untranslated region and an instability sequence in the coding region.

Viral infection of fibroblastic and endothelial cells leads to the transient synthesis of interferon-beta (IFN-beta). The down-regulation of IFN-beta synthesis after infection results both from transcriptional repression of the IFN-beta gene and rapid degradation of mRNA. As with many cytokine mRNAs, IFN-beta mRNA contains an AU-rich element (ARE) in its 3'-untranslated region (UTR). AREs are known to mediate mRNA deadenylation and destabilization. Depending on the class of ARE, deadenylation was shown to occur through synchronous or asynchronous mechanisms. In this study, we analysed IFN-beta mRNA deadenylation in natural conditions of IFN-beta synthesis, e.g. after viral infection. We show that human IFN-beta mRNA follows an asynchronous deadenylation pathway typical of a mRNA containing a class II ARE. A deletion analysis of the IFN-beta natural transcript demonstrates that poly(A) shortening can be mediated by the ARE but also by a 32 nucleotide-sequence located in the coding region, that was identified previously as an instability determinant. In fact, these elements are able to act independently as both of them have to be removed to abrogate mRNA deadenylation. Our data also indicate that deadenylation occurs independently of mRNA translation. Moreover, we show that deadenylation of IFN-beta mRNA is not under the control of viral infection as IFN-beta mRNA derived from a constitutively expressed gene cassette is deadenylated in absence of viral infection. Finally, an unidentified nuclear event appears to be a prerequisite for IFN-beta mRNA deadenylation as IFN-beta mRNA introduced directly into the cytoplasm does not undergo deadenylation. In conclusion, our study demonstrates that IFN-beta mRNA poly(A) shortening is under the control of two cis-acting elements recruiting a deadenylating machinery whose activity is independent of translation and viral infection but might require a nuclear event.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

The MEMPHYS project: A large scale water-Cherenkov detector in Europe

International audienceMemphys project presentation during the 14th conference in the Neutrino Telescopes

The MEMPHYS Project

International audienceMEMPHYS is a proposed 0.5 Mton scale Water Cherenkov experiment to be performed deep underground. Possible sites are under study in the European FP7 design study LAGUNA. It is dedicated to nucleon decay, neutrinos from supernovæ, solar and atmospheric neutrinos, as well as neutrinos from a future Super-Beam or β-Beam to measure the mixing angle θ13, the CP violating phase δ and the mass hierarchy. A small-scale prototype, Memphyno, has been constructed with the purpose of serving as a test bench for new photodetection and data acquisition solutions, such as grouped readout system