Microstructure and chemical composition of Roman orichalcum coins emitted after the monetary reform of Augustus (23 B.C.)

A collection of ancient Roman orichalcum coins, i.e., a copper-zinc alloy, minted under the reigns from Caesar to Domitianus, have been characterised using scanning electron microscopy (SEM-EDS) and electron microprobe analysis (EMPA). We studied, for the first time, coins emitted by Romans after the reforms of Augustus (23 B.C.) and Nero (63-64 A.D). These coins, consisting of asses, sestertii, dupondii and semisses, were analysed using non- and invasive analyses, aiming to explore microstructure, corrosive process and to acquire quantitative chemical analysis. The results revealed that the coins are characterized by porous external layers, which are affected by dezincification and decuprification processes. As pictured by the X-ray maps, the elemental distribution of Cu and Zn shows patterns of depletion that in some cases penetrate in deep up to 1 mm. The composition of the un-corroded nucleus is a Cu-Zn alloy containing up to 30% of Zn, typical of coins produced via cementation process

Sensitivity study of forecasted aftershock seismicity based on Coulomb stress calculation and rate- and state-dependent frictional response

We use the Dieterich (1994) physics-based approach to simulate the spatio- temporal evolution of seismicity caused by stress changes applied to an infinite population of nucleating patches modeled through a rate- and state- dependent friction law. According to this model, seismicity rate changes depend on the amplitude of stress perturbation, the physical constitutive properties of faults (represented by the parameter Aσ), the stressing rate and the background seismicity rate of the study area. In order to apply this model in a predictive manner, we need to understand the impact of physical model parameters and the correlations between them. Firstly we discuss different definitions of the reference seismicity rate and show their impact on the computed rate of earthquake production for the 1992 Landers earthquake sequence as a case study. Furthermore, we demonstrate that all model parameters are strongly correlated for physical and statistical reasons. We discuss this correlation emphasizing that the estimations of the background seismicity rate, stressing rate and Aσ are strongly correlated to reproduce the observed aftershock productivity. Our analytically derived relation demonstrates the impact of these model parameters on the Omori-like aftershock decay: the c- value and the productivity of the Omori law, implying a p-value smaller or equal to 1. Finally, we discuss an optimal strategy to constrain model parameters for near-real time forecasts

Detecting aseismic strain transients from seismicity data

Author Posting. © American Geophysical Union, 2011. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research 116 (2011): B06305, doi:10.1029/2010JB007537.Aseismic deformation transients such as fluid flow, magma migration, and slow slip can trigger changes in seismicity rate. We present a method that can detect these seismicity rate variations and utilize these anomalies to constrain the underlying variations in stressing rate. Because ordinary aftershock sequences often obscure changes in the background seismicity caused by aseismic processes, we combine the stochastic Epidemic Type Aftershock Sequence model that describes aftershock sequences well and the physically based rate- and state-dependent friction seismicity model into a single seismicity rate model that models both aftershock activity and changes in background seismicity rate. We implement this model into a data assimilation algorithm that inverts seismicity catalogs to estimate space-time variations in stressing rate. We evaluate the method using a synthetic catalog, and then apply it to a catalog of M ≥ 1.5 events that occurred in the Salton Trough from 1990 to 2009. We validate our stressing rate estimates by comparing them to estimates from a geodetically derived slip model for a large creep event on the Obsidian Buttes fault. The results demonstrate that our approach can identify large aseismic deformation transients in a multidecade long earthquake catalog and roughly constrain the absolute magnitude of the stressing rate transients. Our method can therefore provide a way to detect aseismic transients in regions where geodetic resolution in space or time is poor.This work was supported by NSF EAR grant 0738641 and USGS NEHRP grant G10AP00004

Genetic landscape of 6089 inherited retinal dystrophies affected cases in Spain and their therapeutic and extended epidemiological implications

Inherited retinal diseases (IRDs), defined by dysfunction or progressive loss of photoreceptors, are disorders characterized by elevated heterogeneity, both at the clinical and genetic levels. Our main goal was to address the genetic landscape of IRD in the largest cohort of Spanish patients reported to date. A retrospective hospital-based cross-sectional study was carried out on 6089 IRD affected individuals (from 4403 unrelated families), referred for genetic testing from all the Spanish autonomous communities. Clinical, demographic and familiar data were collected from each patient, including family pedigree, age of appearance of visual symptoms, presence of any systemic findings and geographical origin. Genetic studies were performed to the 3951 families with available DNA using different molecular techniques. Overall, 53.2% (2100/3951) of the studied families were genetically characterized, and 1549 different likely causative variants in 142 genes were identified. The most common phenotype encountered is retinitis pigmentosa (RP) (55.6% of families, 2447/4403). The most recurrently mutated genes were PRPH2, ABCA4 and RS1 in autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL) NON-RP cases, respectively; RHO, USH2A and RPGR in AD, AR and XL for non-syndromic RP; and USH2A and MYO7A in syndromic IRD. Pathogenic variants c.3386G > T (p.Arg1129Leu) in ABCA4 and c.2276G > T (p.Cys759Phe) in USH2A were the most frequent variants identified. Our study provides the general landscape for IRD in Spain, reporting the largest cohort ever presented. Our results have important implications for genetic diagnosis, counselling and new therapeutic strategies to both the Spanish population and other related populations.This work was supported by the Instituto de Salud Carlos III (ISCIII) of the Spanish Ministry of Health (FIS; PI16/00425 and PI19/00321), Centro de Investigación Biomédica en Red Enfermedades Raras (CIBERER, 06/07/0036), IIS-FJD BioBank (PT13/0010/0012), Comunidad de Madrid (CAM, RAREGenomics Project, B2017/BMD-3721), European Regional Development Fund (FEDER), the Organización Nacional de Ciegos Españoles (ONCE), Fundación Ramón Areces, Fundación Conchita Rábago and the University Chair UAM-IIS-FJD of Genomic Medicine. Irene Perea-Romero is supported by a PhD fellowship from the predoctoral Program from ISCIII (FI17/00192). Ionut F. Iancu is supported by a grant from the Comunidad de Madrid (CAM, PEJ-2017-AI/BMD7256). Marta del Pozo-Valero is supported by a PhD grant from the Fundación Conchita Rábago. Berta Almoguera is supported by a Juan Rodes program from ISCIII (JR17/00020). Pablo Minguez is supported by a Miguel Servet program from ISCIII (CP16/00116). Marta Corton is supported by a Miguel Servet program from ISCIII (CPII17/00006). The funders played no role in study design, data collection, data analysis, manuscript preparation and/or publication decisions

Alpha-protein kinase 3 (ALPK3)-truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy.

AIMS: The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies. METHODS AND RESULTS : In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.01, 95% confidence interval (CI) 7.89-29.74, P < 8.36e-11] compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17, 95% CI 10.31-24.87, P < 2.2e-16, compared to gnomAD). Combined logarithm of odds score in seven families with ALPK3tv was 2.99. In comparison with a cohort of genotyped patients with HCM (n = 1679) with and without pathogenic sarcomere gene variants (SP+ and SP-), ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%, P < 0.001) and of a short PR interval (10%, P = 0.009). Age at diagnosis and maximum left ventricular wall thickness were similar to SP- and left ventricular systolic impairment (6%) and non-sustained ventricular tachycardia (31%) at baseline similar to SP+. After 5.3 ± 5.7 years, 4 (9%) patients with ALPK3tv died of heart failure or had cardiac transplantation (log-rank P = 0.012 vs. SP- and P = 0.425 vs. SP+). Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation. CONCLUSIONS : Heterozygous ALPK3tv are pathogenic and segregate with a characteristic HCM phenotype

The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients

The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the “REGISTRY” cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis