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

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

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

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

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

Value of ultrasonography as a marker of early response to abatacept in patients with rheumatoid arthritis and an inadequate response to methotrexate: results from the APPRAISE study

Objectives: To study the responsiveness of a combined power Doppler and greyscale ultrasound (PDUS) score for assessing synovitis in biologic-naïve patients with rheumatoid arthritis (RA) starting abatacept plus methotrexate (MTX). Methods: In this open-label, multicentre, single-arm study, patients with RA (MTX inadequate responders) received intravenous abatacept (∼10 mg/kg) plus MTX for 24 weeks. A composite PDUS synovitis score, developed by the Outcome Measures in Rheumatology–European League Against Rheumatism (OMERACT–EULAR)-Ultrasound Task Force, was used to evaluate individual joints. The maximal score of each joint was added into a Global OMERACT–EULAR Synovitis Score (GLOESS) for bilateral metacarpophalangeal joints (MCPs) 2–5 (primary objective). The value of GLOESS containing other joint sets was explored, along with clinical efficacy. Results: Eighty-nine patients completed the 24-week treatment period. The earliest PDUS sign of improvement in synovitis was at week 1 (mean change in GLOESS (MCPs 2–5): −0.7 (95% CIs −1.2 to −0.1)), with continuous improvement to week 24. Early improvement was observed in the component scores (power Doppler signal at week 1, synovial hyperplasia at week 2, joint effusion at week 4). Comparable changes were observed for 22 paired joints and minimal joint subsets. Mean Disease Activity Score 28 (C reactive protein) was significantly reduced from weeks 1 to 24, reaching clinical meaningful improvement (change ≥1.2) at week 8. Conclusions: In this first international prospective study, the composite PDUS score is responsive to abatacept. GLOESS demonstrated the rapid onset of action of abatacept, regardless of the number of joints examined. Ultrasound is an objective tool to monitor patients with RA under treatment. Trial registration number: NCT00767325

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Precambrian Research

p.139-162The Paleoproterozoic structural evolution of the Rio Itapicuru greenstone belt (RIGB, Bahia, Brazil) involves two tectonic events of different natures, both associated with magmatism. The first event (D1) developed in response to NW-SE shortening and was responsible for subhorizontal foliation, NW-SE trending lineation and SE-directed thrusts. D1 was coeval with the emplacement of rare 2130 Ma granodioritic plutons. The D2 tectonic event was characterized by left-lateral strike-slip tectonics, developed on steeply dipping D1 foliation and within numerous N-S elongated ca 2080 Ma plutons. Quartz c-axis analysis within the granites shows that they experienced progressive leftlateral shearing from magmatic to solid-state conditions under decreasing temperatures. This fact, in addition to microstructural arguments, indicates syntectonic emplacement of these plutons. A zone of maximum deformation (the Main Shear Zone) has been identified in the centre of the RIGB on the basis of strain measurements. A tectonic model in which D1 thrusting event initiated basin closure before being replaced by D2 strike-slip motion is proposed. The Main Shear Zone corresponds successively to the main thrust zone and the main wrench fault during D1 and D2 events, respectively. Such a switch from orogen-normal thrusts to orogen-parallel transcurrent movements may represent a common progression during evolution of mountain belts in order to accommodate excess crustal thickness. However, because low-grade metamorphism and low intensity of the deformation demonstrate that excess crustal thickness was not attained, it is argued that granite emplacement and ascent played a significant role in triggering strike-slip tectonics in the RIGB