Multisystem proteinopathy due to a homozygous p.Arg159His VCP mutation : a tale of the unexpected

ObjectiveTo assess the clinical, radiologic, myopathologic, and proteomic findings in a patient manifesting a multisystem proteinopathy due to a homozygous valosin-containing protein gene (VCP) mutation previously reported to be pathogenic in the heterozygous state.MethodsWe studied a 36-year-old male index patient and his father, both presenting with progressive limb-girdle weakness. Muscle involvement was assessed by MRI and muscle biopsies. We performed whole-exome sequencing and Sanger sequencing for segregation analysis of the identified p.Arg159His VCP mutation. To dissect biological disease signatures, we applied state-of-the-art quantitative proteomics on muscle tissue of the index case, his father, 3 additional patients with VCP-related myopathy, and 3 control individuals.ResultsThe index patient, homozygous for the known p.Arg159His mutation in VCP, manifested a typical VCP-related myopathy phenotype, although with a markedly high creatine kinase value and a relatively early disease onset, and Paget disease of bone. The father exhibited a myopathy phenotype and discrete parkinsonism, and multiple deceased family members on the maternal side of the pedigree displayed a dementia, parkinsonism, or myopathy phenotype. Bioinformatic analysis of quantitative proteomic data revealed the degenerative nature of the disease, with evidence suggesting selective failure of muscle regeneration and stress granule dyshomeostasis.ConclusionWe report a patient showing a multisystem proteinopathy due to a homozygous VCP mutation. The patient manifests a severe phenotype, yet fundamental disease characteristics are preserved. Proteomic findings provide further insights into VCP-related pathomechanisms

Efficient Experimental and Data-Centered Workflow for Microstructure-Based Fatigue Data – Towards a Data Basis for Predictive AI Models

Background Early fatigue mechanisms for various materials are yet to be unveiled for the (very) high-cycle fatigue (VHCF) regime. This can be ascribed to a lack of available data capturing initial fatigue damage evolution, which continues to adversely affect data scientists and computational modeling experts attempting to derive microstructural dependencies from small sample size data and incomplete feature representations. Objective The aim of this work is to address this lack and to drive the digital transformation of materials such that future virtual component design can be rendered more reliable and more efficient. Achieving this relies on fatigue models that comprehensively capture all relevant dependencies. Methods To this end, this work proposes a combined experimental and data post-processing workflow to establish multimodal fatigue crack initiation and propagation data sets efficiently. It evolves around fatigue testing of mesoscale specimens to increase damage detection sensitivity, data fusion through multimodal registration to address data heterogeneity, and image-based data-driven damage localization. Results A workflow with a high degree of automation is established, that links large distortion-corrected microstructure data with damage localization and evolution kinetics. The workflow enables cycling up to the VHCF regime in comparatively short time spans, while maintaining unprecedented time resolution of damage evolution. Resulting data sets capture the interaction of damage with microstructural features and hold the potential to unravel a mechanistic understanding. Conclusions The proposed workflow lays the foundation for future data mining and data-driven modeling of microstructural fatigue by providing statistically meaningful data sets extendable to a wide range of materials

Does exercise-induced myocardial ischaemia cause enhanced platelet activation and fibrin formation in patients with stable angina and severe coronary artery disease?

In this study, betathromboglobulin (BTG) and fibrinopeptide A (FPA) in peripheral venous blood were measured in 20 patients with stable angina pectoris before and immediately after exercise-induced myocardial ischaemia; in 5 of the 20 patients stable angina was associated with typical peripheral artery disease. A total of 10 patients with angiographically documented peripheral artery disease without angina and 10 normal volunteers were taken as control groups. BTG and FPA in the 15 patients with stable angina before exercise were 41±14 ng ml-1 and 2.3±09 ng ml-1 and were not statistically different from the values in normal controls; after exercise-induced myocardial ischaemia no significant increase occurred in these patients. Conversely, in the 5 patients with stable angina associated with peripheral artery disease BTG and FPA before exercise were 6l±10 ng ml-1 and 3.5±0.8 ng ml-1 and increased to 114±14 ng ml-1 (P<0.001) and 4.l±0.5 ng ml-1 (P<0.01): These results were similar to those found in the 10 patients with isolated peripheral artery disease. We conclude that BTG and FPA in peripheral venous blood in patients with stable angina are not elevated either at rest or after exercise-induced myocardial ischaemia. Elevated values of BTG and FPA in patients with stable angina may reflect a major interaction between blood and atherosclerotic vessel wall, suggesting the presence of associated atherosclerotic lesions in peripheral artery diseas

Direct evidence for significant spin-polarization of EuS in Co/EuS multilayers at room temperature

The new era of spintronics promises the development of nanodevices, where the electron spin will be used to store information and charge currents will be replaced by spin currents. For this, ferromagnetic semiconductors at room temperature are needed. We report on significant room-temperature spin polarization of EuS in Co/EuS multilayers recorded by x-ray magnetic circular dichroism (XMCD). The films were found to contain a mixture of divalent and trivalent europium, but only Eu11 is responsible for the ferromagnetic behavior of EuS. The magnetic XMCD signal of Eu at room temperature could unambiguously be assigned to magnetic ordering of EuS and was found to be only one order of magnitude smaller than that at 2.5 K. The room temperature magnetic moment of EuS is as large as the one of bulk ferromagnetic Ni. Our findings pave the path for fabrication of room–temperature spintronic devices using spin polarized EuS layers

Fibrin formation and platelet activation in patients with myocardial infarction and normal coronary arteries

Coronary spasm is the mechanism most often postulated to explain the rare combination of myocardial infarction and angiographically normal coronary arteries, although the reported evidence for its role is circumstantial rather than conclusive. Whereas the importance of thrombosis in myocardial infarction is uncontested in the presence of significant coronary artery disease, there is little in vivo evidence for thrombosis in angiographically normal coronary arteries. Among 11 consecutive patients with acute myocardial infarction undergoing thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) 3.2 ± 0.7h after onset of chest pain, and angiography 10.2 ± 4.5 days later, three young men had normal coronary arteries. Their cases are documented electrocadiographically, enzymatically and angiographically. Mean plasma levels of fibrinopeptide A (FPA) and beta-thromboglobulin (BTG) were clearly elevated before and during rtPA therapy: FPA 52 ± 41 ng ml-1, BTG 257 ± 46 ng ml-1. They did not differ significantly from corresponding mean plasma levels in the eight patients with severe coronary artery disease: FPA 67 ± 66 ng ml-1, BTG 181 ± 75 ng ml-1. We conclude that fibrin formation and platelet activation are probably equally important in the early hours of myocardial infarction, whether or not significant coronary artery disease is presen

Lifetimes of image-potential states on copper surfaces

The lifetime of image states, which represent a key quantity to probe the coupling of surface electronic states with the solid substrate, have been recently determined for quantum numbers $n\le 6$ on Cu(100) by using time-resolved two-photon photoemission in combination with the coherent excitation of several states (U. H\"ofer et al, Science 277, 1480 (1997)). We here report theoretical investigations of the lifetime of image states on copper surfaces. We evaluate the lifetimes from the knowledge of the self-energy of the excited quasiparticle, which we compute within the GW approximation of many-body theory. Single-particle wave functions are obtained by solving the Schr\"odinger equation with a realistic one-dimensional model potential, and the screened interaction is evaluated in the random-phase approximation (RPA). Our results are in good agreement with the experimentally determined decay times.Comment: 4 pages, 1 figure, to appear in Phys. Rev. Let

Proximity effecs and curie temperature enhancement in Co/EuS and Fe/EuS multilayers

Two identical Co/EuS and Fe/EuS multilayers of six periods each and with individual layers of about 4 nm thick are grown by e-beam evaporation under ultrahigh vacuum conditions. The films show polycrystalline structure with a grain size limited by the individual layer thickness. Both multilayers consist of almost continuous layers with some roughness. The surface peak-to-peak roughness is about 4–5 nm. Magnetization measurements and calculations of the loops based on a Stoner–Wohlfarth-like model allow us to determine the direct antiferromagnetic exchange coupling constant between the 3d metal and EuS at 5 K. Both samples show strong enhancement of the Curie temperature of EuS up to at least 50 K with a EuS magnetization tail, which persists up to about 100 K. The J = 7/2 character of the EuS layers is shown to be responsible for the large Curie temperature enhancement