The Nuclear Ribonucleoprotein SmD1 Interplays with Splicing, RNA Quality Control, and Posttranscriptional Gene Silencing in Arabidopsis

RNA quality control (RQC) eliminates aberrant RNAs based on their atypical structure, whereas posttranscriptional gene silencing (PTGS) eliminates both aberrant and functional RNAs through the sequence-specific action of short interfering RNAs (siRNAs). The Arabidopsis thaliana mutant smd1b was identified in a genetic screen for PTGS deficiency, revealing the involvement of SmD1, a component of the Smith (Sm) complex, in PTGS. The smd1a and smd1b single mutants are viable, but the smd1a smd1b double mutant is embryo-lethal, indicating that SmD1 function is essential. SmD1b resides in nucleoli and nucleoplasmic speckles, colocalizing with the splicing-related factor SR34. Consistent with this, the smd1b mutant exhibits intron retention at certain endogenous mRNAs. SmD1 binds to RNAs transcribed from silenced transgenes but not nonsilenced ones, indicating a direct role in PTGS. Yet, mutations in the RQC factors UPFRAMESHIFT3, EXORIBONUCLEASE2 (XRN2), XRN3, and XRN4 restore PTGS in smd1b, indicating that SmD1 is not essential for but rather facilitates PTGS. Moreover, the smd1b mtr4 double mutant is embryo-lethal, suggesting that SmD1 is essential for mRNA TRANSPORT REGULATOR4-dependent RQC. These results indicate that SmD1 interplays with splicing, RQC, and PTGS. We propose that SmD1 facilitates PTGS by protecting transgene-derived aberrant RNAs from degradation by RQC in the nucleus, allowing sufficient amounts to enter cytoplasmic siRNA bodies to activate PTGS

Profiling the landscape of transcription, chromatin accessibility and chromosome conformation of cattle, pig, chicken and goat genomes [FAANG pilot project]

Functional annotation of livestock genomes is a critical and obvious next step to derive maximum benefit for agriculture, animal science, animal welfare and human health. The aim of the Fr-AgENCODE project is to generate multi-species functional genome annotations by applying high-throughput molecular assays on three target tissues/cells relevant to the study of immune and metabolic traits. An extensive collection of stored samples from other tissues is available for further use (FAANG Biosamples ‘FR-AGENCODE’). From each of two males and two females per species (pig, cattle, goat, chicken), strand-oriented RNA-seq and chromatin accessibility ATAC-seq assays were performed on liver tissue and on two T-cell types (CD3+CD4+&CD3+CD8+) sorted from blood (mammals) or spleen (chicken). Chromosome Conformation Capture (in situ Hi-C) was also carried out on liver. Sequencing reads from the 3 assays were processed using standard processing pipelines. While most (50–70%) RNA-seq reads mapped to annotated exons, thousands of novel transcripts and genes were found, including extensions of annotated protein-coding genes and new lncRNAs (see abstract #69857). Consistency of ATAC-seq results was confirmed by the significant proportion of called peaks in promoter regions (36–66%) and by the specific accumulation pattern of peaks around gene starts (TSS) v. gene ends (TTS). Principal Component Analyses for RNA-seq (based on quantified gene expression) and ATAC-seq (based on quantified chromatin accessibility) highlighted clusters characterised by cell type and sex in all species. From Hi-C data, we generated 40kb-resolution interaction maps, profiled a genome-wide Directionality Index and identified from 4,100 (chicken) to 12,100 (pig) topologically-associating do- mains (TADs). Correlations were reported between RNA-seq and ATAC-seq results (see abstract #71581). In summary, we present here an overview of the first multi-species and -tissue annotations of chromatin accessibility and genome architecture related to gene expression for farm animals

Accueil des adolescents dans un service de psychiatrie adulte de secteur :intérêts et limites (études sur 8 ans)

LE KREMLIN-B.- PARIS 11-BU Méd (940432101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

A New Pathogenic Missense Variant in a Consanguineous North-African Family Responsible for a Highly Variable Aceruloplasminemia Phenotype: A Case-Report

International audienceAceruloplasminemia is a rare autosomal recessive inherited disorder. Mutations in the ceruloplasmin gene cause depressed ferroxidase activity leading to iron accumulation. The clinical phenotype is highly variable: anemia, retinopathy, diabetes mellitus, psychiatric disorders, and neurological symptoms including parkinsonian disorders and dementia are the main features of this disease. Characterized by high serum ferritin with low transferrin saturation, aceruloplasminemia uniquely combines brain, liver and systemic iron overload. We report here four new cases of aceruloplasminemia in a consanguineous North-African family. Genetic sequencing revealed a homozygous missense variant c.656T>A in exon 4 of the ceruloplasmin gene, which had been described previously as of "unknown significance" in the dbSNP database and never associated with ACP in the HGMD database. Ferroxidase activity was strongly depressed. Clinical manifestations varied among cases. The proband exhibited mild microcytic anemia, diabetes mellitus, psychosis and parkinsonism, whereas the other cases were asymptomatic or mildly anemic, although high serum ferritin and brain iron deposition were documented in all of them. Therapeutic management was complex. The proband started deferoxamine treatment when already symptomatic and he rapidly declined. In the asymptomatic cases, the treatment was associated with poor tolerance and was discontinued due to anemia requiring red blood cell transfusion. Our series illustrates the need for new therapeutic approaches to aceruloplasminemia

Cytoplasmic and nuclear quality control and turnover of single-stranded RNA modulate post-transcriptional gene silencing in plants

Eukaryotic RNA quality control (RQC) uses both endonucleolytic and exonucleolytic degradation to eliminate dysfunctional RNAs. In addition, endogenous and exogenous RNAs are degraded through post-transcriptional gene silencing (PTGS), which is triggered by the production of double-stranded (ds)RNAs and proceeds through short-interfering (si)RNA-directed ARGONAUTE-mediated endonucleolytic cleavage. Compromising cytoplasmic or nuclear 5'-3' exoribonuclease function enhances sense-transgene (S)-PTGS in Arabidopsis, suggesting that these pathways compete for similar RNA substrates. Here, we show that impairing nonsense-mediated decay, deadenylation or exosome activity enhanced S-PTGS, which requires host RNA-dependent RNA polymerase 6 (RDR6/SGS2/SDE1) and SUPPRESSOR OF GENE SILENCING 3 (SGS3) for the transformation of single-stranded RNA into dsRNA to trigger PTGS. However, these RQC mutations had no effect on inverted-repeat-PTGS, which directly produces hairpin dsRNA through transcription. Moreover, we show that these RQC factors are nuclear and cytoplasmic and are found in two RNA degradation foci in the cytoplasm: siRNA-bodies and processing-bodies. We propose a model of single-stranded RNA tug-of-war between RQC and S-PTGS that ensures the correct partitioning of RNA substrates among these RNA degradation pathways

Non-invasive measurement of liver iron concentration using 3-Tesla magnetic resonance imaging validation against biopsy

International audienceObjectives - To evaluate the performance and limitations of the R2* and signal intensity ratio (SIR) methods for quantifying liver iron concentration (LIC) at 3 T.Methods - A total of 105 patients who underwent a liver biopsy with biochemical LIC (LIC) were included prospectively. All patients underwent a 3-T MRI scan with a breath-hold multiple-echo gradient-echo sequence (mGRE). LIC calculated by 3-T SIR algorithm (LIC) and by R2* (LIC) were correlated with LIC. Sensitivity and specificity were calculated. The comparison of methods was analysed for successive classes.Results - LIC was strongly correlated with R2* (r = 0.95, p Conclusions - At 3 T, R2* provides precise LIC quantification for lower overload but the SIR method is recommended to overcome R2* limitations in higher overload. Our software, available at www.mrquantif.org , uses both methods jointly and selects the best one.Key points - • Liver iron can be accurately quantified by MRI at 3 T • At 3 T, R2* provides precise quantification of slight liver iron overload • At 3 T, SIR method is recommended in case of high iron overload • Slight liver iron overload present in metabolic syndrome can be depicted • Treatment can be monitored with great confidence.<br

Fluvial geomorphology and flood-risk management

This paper focuses on the contribution of fluvial geomorphology to flood management. We define what fluvial geomorphologists understand by “fluvial risk” and examine the relationship between fluvial geomorphology and fluvial hazards. The paper details how fluvial geomorphology can present innovative approaches to flood prevention, river maintainance and floodplain restoration. Management of soil erosion and floodwaters is the key question in the plateaus and plains of northern France. In mountainous terrain, strong connectivity between the slopes and high order streams induces permanent risk for local people living near the river, on alluvial fans or on the lower river terraces as demonstrated in the French Alps and in Nepal Himalayas. Management of debris flows resulting from interaction of erosion processes on the slopes and valley bottom is of fundamental importance. The paper highlights the diversity of concepts and methods, such as hydrogeomorphological mapping, sediment budget and functional flood areas, developed by fluvial geomorphologists in order to understand spatio-temporal variability of flood hazard and induced flood risk in temperate, Mediterranean and mountainous areas. The discussion places the existing research in the context of the main ecological issues, future climate change and the constraints imposed by the land-use conflicts, political and social choices and the need to preserve natural heritage.Cet article fait le bilan des compétences des hydrogéomorphologues en matière d’analyse des risques fluviaux. Après avoir précisé ce que les hydrogéomorphologues entendent par « risque fluvial » et les connexions existant entre l’hydrogéomorphologie et les aléas de crue, l’article fait état des connaissances produites par les hydrogéomorphologues et comment leur production scientifique peut être mise à profit afin de proposer des actions innovantes en matière de prévention contre les crues, d’entretien des lits de rivière et de restauration des plaines alluviales. L'érosion des sols et la gestion des eaux fluviales sont les éléments clés de la gestion des risques dans les plateaux et les plaines du nord de la France. En régions de montagne, la connexion très forte entre les versants et le lit torrentiel, démontrée ici à travers les cas des Alpes françaises et de l'Himalaya du Népal, induit un risque permanent pour les populations locales vivant près de la rivière, sur les cônes torrentiels ou sur les basses terrasses. Ainsi, la gestion des flux de débris, résultant de l'interaction des processus d'érosion sur les versants et le fond de vallée, est fondamentale dans les montagnes. L'article met en évidence la diversité des concepts et des méthodes, comme la cartographie hydrogéomorphologique, les budgets sédimentaires et l'espace de liberté, développés par les hydrogéomorphologues dans le but de comprendre la variabilité spatio-temporelle des aléas de crue et des risques induits dans les zones tempérées, méditerranéennes et montagneuses. L’apport des recherches actuelles est replacé dans le cadre des grands enjeux écologiques de demain, des changements climatiques et des limites imposées par les conflits d’usage, les choix politiques et sociaux et la préservation du patrimoine

A novel N491S mutation in the human SLC11A2 gene impairs protein trafficking and in association with the G212V mutation leads to microcytic anemia and liver iron overload.

International audienceBACKGROUND: DMT1 is a transmembrane iron transporter involved in iron duodenal absorption and cellular iron uptake. Mutations in the human SLC11A2 gene coding DMT1 lead to microcytic anemia and hepatic iron overload, with unexpectedly low levels of plasma ferritin in the presence of iron stores. DESIGN AND METHODS: We report a patient with a similar phenotype due to two mutations in the SLC11A2 gene, the known p.Gly212Val (G212V) mutation and a novel one, p.Asn491Ser (N491S). To assess the expression of DMT1 in human liver, we studied the expression of the four DMT1 mRNA isoforms by real-time quantitative PCR in control human liver samples. We also studied the effect of G212V and N491S DMT1 mutations on RNA splicing in blood leukocytes and cellular trafficking of dsRed2-tagged-DMT1 protein in the human hepatic cell line HuH7. RESULTS: Our results showed that i) only the isoforms 1B-IRE and 1B-nonIRE were significantly expressed in human liver; ii) the G212V mutation did not seem to affect mRNA splicing and the N491S mutation induced a splicing alteration leading to a truncated protein, which seemed quantitatively of low relevance; and iii) the N491S mutation, in contrast to the G212V mutation, led to abnormal protein trafficking. CONCLUSIONS: Our data confirm the major role of DMT1 in the maintenance of iron homeostasis in humans and demonstrate that the N491S mutation, through its deleterious effect on protein trafficking, contributes together with the G212V mutation to the development of anemia and hepatic iron overload