U-Pb zircon age of 548 Ma for the leptynites (high-grade felsic rocks) of the central part of the Maures Massif. Geodynamic significance of the so-called leptyno-amphibolitic complexes of the Variscan belt of western Europe

Le complexe leptyno-amphibolitique de la partie centrale du massif des Maures a fait l’objet d’une étude géochronologique U-Pb sur zircons et Rb-Sr, et isotopique Sm-Nd. La mise en place du protolithe des leptynites a été datée à 548 Ma, âge nettement plus ancien que ceux (Ordovicien inférieur) mesurés sur d’autres complexes leptyno-amphibolitiques. L’étude Rb-Sr sur roches totales et minéraux séparés a permis de dater l’amphibolitisation à 348 Ma. Les isotopes du Nd montrent que les amphibolites ont des signatures nettement mantelliques. Les trois faciès acides analysés portent une empreinte crustale relativement importante. L’un d’entre eux peut être interprêté comme un mélange simple entre deux sources, respectivement similaires à celle des amphibolites et à celle des deux autres leptynites. Ces dernières, quant à elles, témoignent d’un apport d’une autre source mantellique, distincte de celle des amphibolites, probablement du type basalte alcalin continental. Les résultats obtenus indiquent que les Maures centrales et le sud du Massif central faisaient peut-être partie de la même unité structurale pré-Varisque. L’absence d’indice de lien génétique clair entre les protolithes des deux termes du complexe leptyno-amphibolitique repose le problème de la signification géodynamique de ces formations

Competing English, Spanish, and French alabaster trade in Europe over five centuries as evidenced by isotope fingerprinting

A lack of written sources is a serious obstacle in the reconstruction of the medieval trade of art and art materials, and in the identification of artists, workshop locations, and trade routes. We use the isotopes of sulfur, oxygen, and strontium (S, O, Sr) present in gypsum alabaster to unambiguously link ancient European source quarries and areas to alabaster artworks produced over five centuries (12th–17th) held by the Louvre museum in Paris and other European and American collections. Three principal alabaster production areas are identified, in central England, northern Spain, and a major, long-lived but little-documented alabaster trade radiating from the French Alps. The related trade routes are mostly fluvial, although terrestrial transport crossing the major river basin borders is also confirmed by historical sources. Our study also identifies recent artwork restoration using Italian alabaster and provides a robust geochemical framework for provenancing, including recognition of restoration and forgeries

Mineralogical and isotopic record of biotic and abiotic diagenesis of the Callovian-Oxfordian clayey formation of Bure (France)

International audienceThe Callovian-Oxfordian (COx) clayey unit is being studied in the Eastern part of the Paris Basin at depths between 400 and 500 m depth to assess of its suitability for nuclear waste disposal. The present study combines new mineralogical and isotopic data to describe the sedimentary history of the COx unit. Petrologic study provided evidence of the following diagenetic mineral sequence: (1) framboidal pyrite and micritic calcite, (2) iron-rich euhedral carbonates (ankerite, sideroplesite) and glauconite (3) limpid calcite and dolomite and celestite infilling residual porosity in bioclasts and cracks, (4) chalcedony, (5) quartz/calcite. Pyrite in bioturbations shows a wide range of δ34S (−38‰ to +34.5‰), providing evidence of bacterial sulphate reduction processes in changing sedimentation conditions. The most negative values (−38‰ to −22‰), measured in the lower part of the COx unit indicate precipitation of pyrite in a marine environment with a continuous sulphate supply. The most positive pyrite δ34S values (−14‰ up to +34.5‰) in the upper part of the COx unit indicate pyrite precipitation in a closed system. Celestite δ34S values reflect the last evolutionary stage of the system when bacterial activity ended; however its deposition cannot be possible without sulphate supply due to carbonate bioclast dissolution. The 87Sr/86Sr ratio of celestite (0.706872-0.707040) is consistent with deposition from Jurassic marine-derived waters. Carbon and oxygen isotopic compositions of bulk calcite and dolomite are consistent with marine carbonates. Siderite, only present in the maximum clay zone, has chemical composition and δ18O consistent with a marine environment. Its δ13C is however lower than those of marine carbonates, suggesting a contribution of 13C-depleted carbon from degradation of organic matter. δ18O values of diagenetic chalcedony range between +27‰ and +31‰, suggesting precipitation from marine-derived pore waters. Late calcite crosscutting a vein filled with chalcedony and celestite, and late euhedral quartz in a limestone from the top of the formation have lower δ18O values (not, vert, similar+19‰), suggesting that they precipitated from meteoric fluids, isotopically close to present-day pore waters of the formation. Finally, the study illustrates the transition from very active, biotic diagenesis to abiotic diagenesis. This transition appears to be driven by compaction of the sediment, which inhibited movement of bacterial cells by reduction of porosity and pore sizes, rather than a lack of inorganic carbon or sulphates

Tracing Medieval and Renaissance Alabaster Works of Art Back to Quarries: A Multi-Isotope (Sr, S, O) Approach

Multi-isotope fingerprinting (sulphur, oxygen and strontium isotopes) has been tested to study the provenances of medieval and Renaissance French and Swedish alabaster works of art. Isotope signatures of historical English, French and Spanish alabaster source quarries or areas are revealed to be highly specific, with a strong intra-group homogeneity and strong inter-group contrasts, especially for Sr and S isotopes. The chosen combination of isotope tracers is a good basis for forensic work on alabaster provenance, allowing verification of hypotheses about historical trade routes as well as identification of fakes and their origin. The applied analytical techniques of continuous flow isotope ratio mass spectrometry (CF–IRMS) and thermal ionization mass spectrometry (TIMS) only require micro-samples in the low-milligram range, thus minimizing the impact on the works of art

Identification of Periostin as a Critical Marker of Progression/Reversal of Hypertensive Nephropathy

Progression of chronic kidney disease (CKD) is a major health issue due to persistent accumulation of extracellular matrix in the injured kidney. However, our current understanding of fibrosis is limited, therapeutic options are lacking, and progressive degradation of renal function prevails in CKD patients. Uncovering novel therapeutic targets is therefore necessary

Clinical spectrum of MTOR-related hypomelanosis of Ito with neurodevelopmental abnormalities

PURPOSE: Hypomelanosis of Ito (HI) is a skin marker of somatic mosaicism. Mosaic MTOR pathogenic variants have been reported in HI with brain overgrowth. We sought to delineate further the pigmentary skin phenotype and clinical spectrum of neurodevelopmental manifestations of MTOR-related HI. METHODS: From two cohorts totaling 71 patients with pigmentary mosaicism, we identified 14 patients with Blaschko-linear and one with flag-like pigmentation abnormalities, psychomotor impairment or seizures, and a postzygotic MTOR variant in skin. Patient records, including brain magnetic resonance image (MRI) were reviewed. Immunostaining (n = 3) for melanocyte markers and ultrastructural studies (n = 2) were performed on skin biopsies. RESULTS: MTOR variants were present in skin, but absent from blood in half of cases. In a patient (p.[Glu2419Lys] variant), phosphorylation of p70S6K was constitutively increased. In hypopigmented skin of two patients, we found a decrease in stage 4 melanosomes in melanocytes and keratinocytes. Most patients (80%) had macrocephaly or (hemi)megalencephaly on MRI. CONCLUSION: MTOR-related HI is a recognizable neurocutaneous phenotype of patterned dyspigmentation, epilepsy, intellectual deficiency, and brain overgrowth, and a distinct subtype of hypomelanosis related to somatic mosaicism. Hypopigmentation may be due to a defect in melanogenesis, through mTORC1 activation, similar to hypochromic patches in tuberous sclerosis complex

Loss-of-function variants in CUL3 cause a syndromic neurodevelopmental disorder

Purpose De novovariants inCUL3(Cullin-3 ubiquitin ligase) have been strongly associated with neurodevelopmental disorders (NDDs), but no large case series have been reported so far. Here we aimed to collect sporadic cases carrying rare variants inCUL3,describe the genotype-phenotype correlation, and investigate the underlying pathogenic mechanism.MethodsGenetic data and detailed clinical records were collected via multi-center collaboration. Dysmorphic facial features were analyzed using GestaltMatcher. Variant effects on CUL3 protein stability were assessed using patient-derived T-cells.ResultsWe assembled a cohort of 35 individuals with heterozygousCUL3variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features. Of these, 33 have loss-of-function (LoF) and two have missense variants.CUL3LoF variants in patients may affect protein stability leading to perturbations in protein homeostasis, as evidenced by decreased ubiquitin-protein conjugatesin vitro. Specifically, we show that cyclin E1 (CCNE1) and 4E-BP1 (EIF4EBP1), two prominent substrates of CUL3, fail to be targeted for proteasomal degradation in patient-derived cells.ConclusionOur study further refines the clinical and mutational spectrum ofCUL3-associated NDDs, expands the spectrum of cullin RING E3 ligase-associated neuropsychiatric disorders, and suggests haploinsufficiency via LoF variants is the predominant pathogenic mechanism

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049