Mutations in proteins involved in E-C coupling and SOCE and congenital myopathies

In skeletal muscle, Ca2+ necessary for muscle contraction is stored and released from the sarcoplasmic reticulum (SR), a specialized form of endoplasmic reticulum through the mechanism known as excitation-contraction (E-C) coupling. Following activation of skeletal muscle contraction by the E-C coupling mechanism, replenishment of intracellular stores requires reuptake of cytosolic Ca2+ into the SR by the activity of SR Ca2+-ATPases, but also Ca2+ entry from the extracellular space, through a mechanism called store-operated calcium entry (SOCE). The fine orchestration of these processes requires several proteins, including Ca2+ channels, Ca2+ sensors, and Ca2+ buffers, as well as the active involvement of mitochondria. Mutations in genes coding for proteins participating in E-C coupling and SOCE are causative of several myopathies characterized by a wide spectrum of clinical phenotypes, a variety of histological features, and alterations in intracellular Ca2+ balance. This review summarizes current knowledge on these myopathies and discusses available knowledge on the pathogenic mechanisms of disease

Towards 3d multi-layer scaffolds for periodontal tissue engineering applications: Addressing manufacturing and architectural challenges

Reduced periodontal support, deriving from chronic inflammatory conditions, such as periodontitis, is one of the main causes of tooth loss. The use of dental implants for the replacement of missing teeth has attracted growing interest as a standard procedure in clinical practice. However, adequate bone volume and soft tissue augmentation at the site of the implant are important prerequisites for successful implant positioning as well as proper functional and aesthetic reconstruction of patients. Three-dimensional (3D) scaffolds have greatly contributed to solve most of the challenges that traditional solutions (i.e., autografts, allografts and xenografts) posed. Nevertheless, mimicking the complex architecture and functionality of the periodontal tissue represents still a great challenge. In this study, a porous poly(ε-caprolactone) (PCL) and Sr-doped nano hydroxyapatite (Sr-nHA) with a multi-layer structure was produced via a single-step additive manufacturing (AM) process, as a potential strategy for hard periodontal tissue regeneration. Physicochemical characterization was conducted in order to evaluate the overall scaffold architecture, topography, as well as porosity with respect to the original CAD model. Furthermore, compressive tests were performed to assess the mechanical properties of the resulting multi-layer structure. Finally, in vitro biological performance, in terms of biocompatibility and osteogenic potential, was evaluated by using human osteosarcoma cells. The manufacturing route used in this work revealed a highly versatile method to fabricate 3D multi-layer scaffolds with porosity levels as well as mechanical properties within the range of dentoalveolar bone tissue. Moreover, the single step process allowed the achievement of an excellent integrity among the different layers of the scaffold. In vitro tests suggested the promising role of the ceramic phase within the polymeric matrix towards bone mineralization processes. Overall, the results of this study demonstrate that the approach undertaken may serve as a platform for future advances in 3D multi-layer and patient-specific strategies that may better address complex periodontal tissue defects

Ryanodine receptor 1 (RYR1) mutations in two patients with tubular aggregate myopathy

Two likely causative mutations in the RYR1 gene were identified in two patients with myopathy with tubular aggregates, but no evidence of cores or core-like pathology on muscle biopsy. These patients were clinically evaluated and underwent routine laboratory investigations, electrophysiologic tests, muscle biopsy and muscle magnetic resonance imaging (MRI). They reported stiffness of the muscles following sustained activity or cold exposure and had serum creatine kinase elevation. The identified RYR1 mutations (p.Thr2206Met or p.Gly2434Arg, in patient 1 and patient 2, respectively) were previously identified in individuals with malignant hyperthermia susceptibility and are reported as causative according to the European Malignant Hyperthermia Group rules. To our knowledge, these data represent the first identification of causative mutations in the RYR1 gene in patients with tubular aggregate myopathy and extend the spectrum of histological alterations caused by mutation in the RYR1 gene

Skeletal muscle overexpression of sAnk1.5 in transgenic mice does not predispose to type 2 diabetes

Genome-wide association studies (GWAS) and cis-expression quantitative trait locus (cis-eQTL) analyses indicated an association of the rs508419 single nucleotide polymorphism (SNP) with type 2 diabetes (T2D). rs508419 is localized in the muscle-specific internal promoter (P2) of the ANK1 gene, which drives the expression of the sAnk1.5 isoform. Functional studies showed that the rs508419 C/C variant results in increased transcriptional activity of the P2 promoter, leading to higher levels of sAnk1.5 mRNA and protein in skeletal muscle biopsies of individuals carrying the C/C genotype. To investigate whether sAnk1.5 overexpression in skeletal muscle might predispose to T2D development, we generated transgenic mice (TgsAnk1.5/+) in which the sAnk1.5 coding sequence was selectively overexpressed in skeletal muscle tissue. TgsAnk1.5/+ mice expressed up to 50% as much sAnk1.5 protein as wild-type (WT) muscles, mirroring the difference reported between individuals with the C/C or T/T genotype at rs508419. However, fasting glucose levels, glucose tolerance, insulin levels and insulin response in TgsAnk1.5/+ mice did not differ from those of age-matched WT mice monitored over a 12-month period. Even when fed a high-fat diet, TgsAnk1.5/+ mice only presented increased caloric intake, but glucose disposal, insulin tolerance and weight gain were comparable to those of WT mice fed a similar diet. Altogether, these data indicate that sAnk1.5 overexpression in skeletal muscle does not predispose mice to T2D susceptibility

Distinct behavior of localized and delocalized carriers in anatase TiO2 (001) during reaction with O-2

Two-dimensional (2D) metallic states induced by oxygen vacancies ( V O s ) at oxide surfaces and interfaces provide opportunities for the development of advanced applications, but the ability to control the behavior of these states is still limited. We used angle resolved photoelectron spectroscopy combined with density-functional theory (DFT) to study the reactivity of V O -induced states at the (001) surface of anatase TiO 2 , where both 2D metallic and deeper lying in-gap states (IGs) are observed. The 2D and IG states exhibit remarkably different evolutions when the surface is exposed to molecular O 2 : while IGs are almost completely quenched, the metallic states are only weakly affected. DFT calculations indeed show that the IGs originate from surface V O s and remain localized at the surface, where they can promptly react with O 2 . In contrast, the metallic states originate from subsurface vacancies whose migration to the surface for recombination with O 2 is kinetically hindered on anatase TiO 2 (001), thus making them much less sensitive to oxygen dosing

Observation of Termination-Dependent Topological Connectivity in a Magnetic Weyl Kagome Lattice

Engineering surfaces and interfaces of materials promises great potential in the field of heterostructures and quantum matter designers, with the opportunity to drive new many-body phases that are absent in the bulk compounds. Here, we focus on the magnetic Weyl kagome system Co3Sn2S2 and show how for the terminations of different samples the Weyl points connect differently, still preserving the bulk-boundary correspondence. Scanning tunneling microscopy has suggested such a scenario indirectly, and here, we probe the Fermiology of Co3Sn2S2 directly, by linking it to its real space surface distribution. By combining micro-ARPES and first-principles calculations, we measure the energy-momentum spectra and the Fermi surfaces of Co3Sn2S2 for different surface terminations and show the existence of topological features depending on the top-layer electronic environment. Our work helps to define a route for controlling bulk-derived topological properties by means of surface electrostatic potentials, offering a methodology for using Weyl kagome metals in responsive magnetic spintronics

Observation of termination-dependent topological connectivity in a magnetic Weyl Kagome lattice

The research leading to these results has received funding from the European Union’s Horizon 2020 research and innovation program under Marie Skłodowska-Curie Grant Agreement 897276. The authors gratefully acknowledge the Gauss Centre for Supercomputing e.V. (https://www.gauss-centre.eu) for funding this project by providing computing time on the GCS Supercomputer SuperMUC-NG at Leibniz Supercomputing Centre (https://www.lrz.de). The authors are grateful for funding support from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy through the Würzburg-Dresden Cluster of Excellence on Complexity and Topology in Quantum Matter ct.qmat (EXC 2147, Project 390858490), through FOR 5249-449872909 (Project P5), and through the Collaborative Research Center SFB 1170 ToCoTronics (Project 258499086). The authors greatly acknowledge the Diamond Light Source that supported the entire micro-ARPES experiment and corresponding costs. The Flatiron Institute is a division of the Simons Foundation. P.D.C.K. and C.B. gratefully acknowledge support from The Leverhulme Trust via Grant RL-2016-006.Engineering surfaces and interfaces of materials promises great potential in the field of heterostructures and quantum matter designers, with the opportunity to drive new many-body phases that are absent in the bulk compounds. Here, we focus on the magnetic Weyl kagome system Co3Sn2S2 and show how for the terminations of different samples the Weyl points connect differently, still preserving the bulk-boundary correspondence. Scanning tunneling microscopy has suggested such a scenario indirectly, and here, we probe the Fermiology of Co3Sn2S2 directly, by linking it to its real space surface distribution. By combining micro-ARPES and first-principles calculations, we measure the energy-momentum spectra and the Fermi surfaces of Co3Sn2S2 for different surface terminations and show the existence of topological features depending on the top-layer electronic environment. Our work helps to define a route for controlling bulk-derived topological properties by means of surface electrostatic potentials, offering a methodology for using Weyl kagome metals in responsive magnetic spintronics.Publisher PDFPeer reviewe

A survey of Italian and Spanish neonatologists and paediatricians regarding awareness of the diagnosis of FAS and FASD and maternal ethanol use during pregnancy

<p>Abstract</p> <p>Background</p> <p>Ethanol is the most widely used drug in the world and a human teratogen whose consumption among women of childbearing age has been steadily increasing. There are no Italian or Spanish statistics on ethanol consumption during pregnancy nor any information regarding prevalence of fetal alcohol syndrome (FAS) and fetal alcohol spectrum disorders (FASD). There is also a reasonable suspicion that these two diseases are underdiagnosed by professionals from the above-reported countries. The objectives of this study were: 1) to evaluate the experience, knowledge and confidence of Italian and Spanish neonatologists and paediatricians with respect to the diagnosis of FAS and FASD, and 2) to evaluate professionals awareness of maternal drinking patterns during pregnancy.</p> <p>Methods</p> <p>A multiple-choice anonymous questionnaire was e-mailed to Italian neonatologists registered in the mailing list of the corresponding Society and administered to Italian and Spanish paediatricians during their National Congress.</p> <p>Results</p> <p>The response rate was 16% (63/400) for the Italian neonatologists of the National Society while a total of 152 Spanish and 41 Italian paediatricians agreed to complete the questionnaire during National Congress. Over 90% of the surveyed physicians declared that FAS is an identifiable syndrome and over 60% of them identified at least one of the most important features of FAS. Although over 60% Italian responders and around 80% Spanish responders were aware that ethanol use in pregnancy is dangerous, approximately 50% Italian responders and 40% Spanish ones allowed women to drink sometimes a glass of wine or beer during pregnancy.</p> <p>Neonatologists and paediatricians rated confidence in the ability to diagnosis FAS and FASD as low, with over 50% responders feeling they needed more information regarding FAS and FASD identification in newborn and child.</p> <p>Conclusions</p> <p>Italian and Spanish neonatologists and paediatricians do not feel confident about diagnosing FAS and FASD. More training is needed in order to accurately diagnose ethanol use during pregnancy and correctly inform pregnant women on the consequences on the newborn.</p