Étude haute résolution de la distribution et de la granulométrie des constituants organiques sédimentaires dans le Kimméridgien–Tithonien du Boulonnais (Nord de la France). Application à l'analyse séquentielle <br />–––<br />Sedimentary organic matter, accumulation and grain-size in the Kimmeridgian–Tithonian of the Boulonnais area (Northern France). Application to sequence stratigraphy.

La matière organique sédimentaire des formations argileuses du Kimméridgien–Tithonien du Boulonnais a été étudiée sous un aspect multidisciplinaire : pétrographique, géochimique et granulométrique, ainsi que du point de vue de la stratigraphie séquentielle. Les flocons de matière organique amorphe d'origine marine dominent les palynofaciès et leur distribution se corrèle aux variations du COT, du soufre total et des paramètres granulométriques. La forte productivité des eaux de surface a dû induire une intense sulfato-réduction sous l'interface eau–sédiment, pouvant alors provoquer la sulfuration (vulcanisation) de la matière organique sédimentaire d'origine marine, malgré la présence de fer dans le milieu de dépôt. La granulométrie de l'ensemble des particules se corrèle aux variations de ce type de matière organique et aux périodes de haut niveau marin, ce qui serait une nouvelle approche dans la compréhension du découpage séquentiel. The sedimentary organic matter from the Kimmeridgian–Tithonian marlstones of the Boulonnais area is studied through a petrographic, geochemical and a grain-size distribution approach. The abundance of the orange amorphous organic matter (AOM) correlates well with the geochemical parameters and intense sulfurisation reactions could explain its preservation, with a relative iron shortage. This may imply strong surface-water productivity linked to sea-level highstands and a possible decrease in sedimentation rate. The OM grain-size parameters correlate with sea-level variations and the orange AOM distribution in the Argiles de Châtillon formation. This relation could be helpful for the comprehension of the sequential stratigraphy

Organic facies variation in the late Kimmeridgian of the Boulonnais area (northernmost France)

Recent studies of the upper Kimmeridgian of the Boulonnais area (northernmost France) have provided a sequence-stratigraphical framework that is here used to help interpret variations in sedimentary organic matter (OM) content and composition in response to fluctuations in relative sea-level. The organic facies are characterised using a combination of palynofacies, bulk organic geochemistry (TOC, Rock Eval pyrolysis, and sulphur data), and the particle-size distribution of the total palynological residues. The organic facies show a good correlation with the sequence stratigraphy, exhibiting peak TOC, HI, total S and Sorg values in the lithofacies deposited around the two MFS. The palynofacies in these intervals is characterised by a high content of fluorescent, orange, marine AOM. There is a strong correlation between the orange AOM and the total and organic sulphur contents. Similar positive correlations between orange AOM and organic sulphur have previously been observed in the distal organic-rich sediments of the Kimmeridge Clay Formation of Dorset (lateral time equivalents of the Boulonnais facies), but there the sulphur contents are lower, indicating that organic sulphur content of orange AOM is not fixed, suggestive of preservation-related parallel but not intrinsically related trends. The S data can be used to estimate an apparent burial efficiency and hence the proportion of the primary productivity preserved; this allows a rough estimate of palaeoproductivity. Model calculations suggest that for a sulphide retention of 30–70% and uncompacted sedimentation rate estimates in the range 5–10 cm/ka, the mean palaeoproductivity was in the range 52–175 gC/m2/a (up to 6% of which was preserved). Thus, if the preservation is high, as is the case for MFS, the palaeoproductivity does not need to be above average for shelf waters to produce a given TOC

Congenital hydrocephalus : new Mendelian mutations and evidence for oligogenic inheritance

Peer reviewe

Two-year efficacy and safety of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy (SMA)

Risdiplam is an oral, survival of motor neuron 2 (SMN2) pre-mRNA splicing modifier approved for the treatment of spinal muscular atrophy (SMA). SUNFISH (NCT02908685) Part 2, a Phase 3, randomized, double-blind, placebo-controlled study, investigated the efficacy and safety of risdiplam in type 2 and non‑ambulant type 3 SMA. The primary endpoint was met: a significantly greater change from baseline in 32-item Motor Function Measure (MFM32) total score was observed with risdiplam compared with placebo at month 12. After 12 months, all participants received risdiplam while preserving initial treatment blinding. We report 24-month efficacy and safety results in this population. Month 24 exploratory endpoints included change from baseline in MFM32 and safety. MFM‑derived results were compared with an external comparator. At month 24 of risdiplam treatment, 32% of patients demonstrated improvement (a change of ≥ 3) from baseline in MFM32 total score; 58% showed stabilization (a change of ≥ 0). Compared with an external comparator, a treatment difference of 3.12 (95% confidence interval [CI] 1.67-4.57) in favor of risdiplam was observed in MFM-derived scores. Overall, gains in motor function at month 12 were maintained or improved upon at month 24. In patients initially receiving placebo, MFM32 remained stable compared with baseline (0.31 [95% CI - 0.65 to 1.28]) after 12 months of risdiplam; 16% of patients improved their score and 59% exhibited stabilization. The safety profile after 24 months was consistent with that observed after 12 months. Risdiplam over 24 months resulted in further improvement or stabilization in motor function, confirming the benefit of longer-term treatment

Continental weathering as a driver of Late Cretaceous cooling : new insights from clay mineralogy of Campanian sediments from the southern Tethyan margin to the Boreal realm

21 pagesInternational audienceNew clay mineralogical analyses have been performed on Campanian sediments from the Tethyan and Boreal realms along a palaeolatitudinal transect from 45° to 20°N (Danish Basin, North Sea, Paris Basin, Mons Basin, Aquitaine Basin, Umbria-Marche Basin and Tunisian Atlas). Significant terrigenous inputs are evidenced by increasing proportions of detrital clay minerals such as illite, kaolinite and chlorite at various levels in the mid- to upper Campanian, while smectitic minerals predominate and represented the background of the Late Cretaceous clay sedimentation. Our new results highlight a distinct latitudinal distribution of clay minerals, with the occurrence of kaolinite in southern sections and an almost total absence of this mineral in northern areas. This latitudinal trend points to an at least partial climatic control on clay mineral sedimentation, with a humid zone developed between 20° and 35°N. The association and co-evolution of illite, chlorite and kaolinite in most sections suggest a reworking of these minerals from basement rocks weathered by hydrolysis, which we link to the formation of relief around the Tethys due to compression associated with incipient Tethyan closure. Diachronism in the occurrence of detrital minerals between sections, with detrital input starting earlier during the Santonian in the south than in the north, highlights the northward progression of the deformation related to the anticlockwise rotation of Africa. Increasing continental weathering and erosion, evidenced by our clay mineralogical data through the Campanian, may have resulted in enhanced CO2 consumption by silicate weathering, thereby contributing to Late Cretaceous climatic cooling

Detection of variants in dystroglycanopathy-associated genes through the application of targeted whole-exome sequencing analysis to a large cohort of patients with unexplained limb-girdle muscle weakness

Background: Dystroglycanopathies are a clinically and genetically heterogeneous group of disorders that are typically characterised by limb-girdle muscle weakness. Mutations in 18 different genes have been associated with dystroglycanopathies, the encoded proteins of which typically modulate the binding of alpha-dystroglycan to extracellular matrix ligands by altering its glycosylation. This results in a disruption of the structural integrity of the myocyte, ultimately leading to muscle degeneration. Methods: Deep phenotypic information was gathered using the PhenoTips online software for 1001 patients with unexplained limb-girdle muscle weakness from 43 different centres across 21 European and Middle Eastern countries. Whole-exome sequencing with at least 250 ng DNA was completed using an Illumina exome capture and a 38 Mb baited target. Genes known to be associated with dystroglycanopathies were analysed for disease-causing variants. Results: Suspected pathogenic variants were detected in DPM3, ISPD, POMT1 and FKTN in one patient each, in POMK in two patients, in GMPPB in three patients, in FKRP in eight patients and in POMT2 in ten patients. This indicated a frequency of 2.7% for the disease group within the cohort of 1001 patients with unexplained limb-girdle muscle weakness. The phenotypes of the 27 patients were highly variable, yet with a fundamental presentation of proximal muscle weakness and elevated serum creatine kinase. Conclusions: Overall, we have identified 27 patients with suspected pathogenic variants in dystroglycanopathy-associated genes. We present evidence for the genetic and phenotypic diversity of the dystroglycanopathies as a disease group, while also highlighting the advantage of incorporating next-generation sequencing into the diagnostic pathway of rare diseases.Peer reviewe

Computational Study of the Human Dystrophin Repeats: Interaction Properties and Molecular Dynamics

Dystrophin is a large protein involved in the rare genetic disease Duchenne muscular dystrophy (DMD). It functions as a mechanical linker between the cytoskeleton and the sarcolemma, and is able to resist shear stresses during muscle activity. In all, 75% of the dystrophin molecule consists of a large central rod domain made up of 24 repeat units that share high structural homology with spectrin-like repeats. However, in the absence of any high-resolution structure of these repeats, the molecular basis of dystrophin central domain's functions has not yet been deciphered. In this context, we have performed a computational study of the whole dystrophin central rod domain based on the rational homology modeling of successive and overlapping tandem repeats and the analysis of their surface properties. Each tandem repeat has very specific surface properties that make it unique. However, the repeats share enough electrostatic-surface similarities to be grouped into four separate clusters. Molecular dynamics simulations of four representative tandem repeats reveal specific flexibility or bending properties depending on the repeat sequence. We thus suggest that the dystrophin central rod domain is constituted of seven biologically relevant sub-domains. Our results provide evidence for the role of the dystrophin central rod domain as a scaffold platform with a wide range of surface features and biophysical properties allowing it to interact with its various known partners such as proteins and membrane lipids. This new integrative view is strongly supported by the previous experimental works that investigated the isolated domains and the observed heterogeneity of the severity of dystrophin related pathologies, especially Becker muscular dystrophy

Three years pilot of spinal muscular atrophy newborn screening turned into official program in Southern Belgium.

Three new therapies for spinal muscular atrophy (SMA) have been approved by the United States Food and Drug Administration and the European Medicines Agency since 2016. Although these new therapies improve the quality of life of patients who are symptomatic at first treatment, administration before the onset of symptoms is significantly more effective. As a consequence, newborn screening programs have been initiated in several countries. In 2018, we launched a 3-year pilot program to screen newborns for SMA in the Belgian region of Liège. This program was rapidly expanding to all of Southern Belgium, a region of approximately 55,000 births annually. During the pilot program, 136,339 neonates were tested for deletion of exon 7 of SMN1, the most common cause of SMA. Nine SMA cases with homozygous deletion were identified through this screen. Another patient was identified after presenting with symptoms and was shown to be heterozygous for the SMN1 exon 7 deletion and a point mutation on the opposite allele. These ten patients were treated. The pilot program has now successfully transitioned into the official neonatal screening program in Southern Belgium. The lessons learned during implementation of this pilot program are reported