The medical genetics of dystrophinopathies: Molecular genetic diagnosis and its impact on clinical practice

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An Open System for Collection and Automatic Recognition of Pottery through Neural Network Algorithms

In the last ten years, artificial intelligence (AI) techniques have been applied in archaeology. The ArchAIDE project realised an AI-based application to recognise archaeological pottery. Pottery is of paramount importance for understanding archaeological contexts. However, recognition of ceramics is still a manual, time-consuming activity, reliant on analogue catalogues. The project developed two complementary machine-learning tools to propose identifications based on images captured on-site, for optimising and economising this process, while retaining key decision points necessary to create trusted results. One method relies on the shape of a potsherd; the other is based on decorative features. For the shape-based recognition, a novel deep-learning architecture was employed, integrating shape information from points along the inner and outer profile of a sherd. The decoration classifier is based on relatively standard architectures used in image recognition. In both cases, training the algorithms meant facing challenges related to real-world archaeological data: the scarcity of labelled data; extreme imbalance between instances of different categories; and the need to take note of minute differentiating features. Finally, the creation of a desktop and mobile application that integrates the AI classifiers provides an easy-to-use interface for pottery classification and storing pottery data

Persistent Dystrophin Protein Restoration 90 Days after a Course of Intraperitoneally Administered Naked 2′OMePS AON and ZM2 NP-AON Complexes in mdx Mice

In Duchenne muscular dystrophy, the exon-skipping approach has obtained proof of concept in animal models, myogenic cell cultures, and following local and systemic administration in Duchenne patients. Indeed, we have previously demonstrated that low doses (7.5 mg/Kg/week) of 2 -O-methyl-phosphorothioate antisense oligoribonucleotides (AONs) adsorbed onto ZM2 nanoparticles provoke widespread dystrophin restoration 7 days after intraperitoneal treatment in mdx mice. In this study, we went on to test whether this dystrophin restoration was still measurable 90 days from the end of the same treatment. Interestingly, we found that both western blot and immunohistochemical analysis (up to 7% positive fibres) were still able to detect dystrophin protein in the skeletal muscles of ZM2-AON-treated mice at this time, and the level of exon-23 skipping could still be assessed by RT real-time PCR (up to 10% of skipping percentage). In contrast, the protein was undetectable by western blot analysis in the skeletal muscles of mdx mice treated with an identical dose of naked AON, and the percentage of dystrophin-positive fibres and exon-23 skipping were reminiscent of those of untreated mdx mice. Our data therefore demonstrate the long-term residual efficacy of this systemic low-dose treatment and confirm the protective effect nanoparticles exert on AON molecules

Persistent Dystrophin Protein Restoration 90 Days after a Course of Intraperitoneally Administered Naked 2′OMePS AON and ZM2 NP-AON Complexes in mdx Mice

In Duchenne muscular dystrophy, the exon-skipping approach has obtained proof of concept in animal models, myogenic cell cultures, and following local and systemic administration in Duchenne patients. Indeed, we have previously demonstrated that low doses (7.5 mg/Kg/week) of 2  -O-methyl-phosphorothioate antisense oligoribonucleotides (AONs) adsorbed onto ZM2 nanoparticles provoke widespread dystrophin restoration 7 days after intraperitoneal treatment in mdx mice. In this study, we went on to test whether this dystrophin restoration was still measurable 90 days from the end of the same treatment. Interestingly, we found that both western blot and immunohistochemical analysis (up to 7% positive fibres) were still able to detect dystrophin protein in the skeletal muscles of ZM2-AON-treated mice at this time, and the level of exon-23 skipping could still be assessed by RT real-time PCR (up to 10% of skipping percentage). In contrast, the protein was undetectable by western blot analysis in the skeletal muscles of mdx mice treated with an identical dose of naked AON, and the percentage of dystrophin-positive fibres and exon-23 skipping were reminiscent of those of untreated mdx mice. Our data therefore demonstrate the long-term residual efficacy of this systemic low-dose treatment and confirm the protective effect nanoparticles exert on AON molecules

Rapid, comprehensive analysis of the dystrophin transcript by a custom micro-fluidic exome array

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Monoclonal antibodies to murine thrombospondin-1 and thrombospondin-2 reveal differential expression patterns in cancer and low antigen expression in normal tissues

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New Clinical and Immunofluorescence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients

Pathogenetic mechanism recognition and proof-of-concept clinical trials were performed in our patients affected by collagen VI-related myopathies. This study, which included 69 patients, aimed to identify innovative clinical data to better design future trials. Among the patients, 33 had Bethlem myopathy (BM), 24 had Ullrich congenital muscular dystrophy (UCMD), 7 had an intermediate phenotype (INTM), and five had myosclerosis myopathy (MM). We obtained data on muscle strength, the degree of contracture, immunofluorescence, and genetics. In our BM group, only one third had a knee extension strength greater than 50% of the predicted value, while only one in ten showed similar retention of elbow flexion. These findings should be considered when recruiting BM patients for future trials. All the MM patients had axial and limb contractures that limited both the flexion and extension ranges of motion, and a limitation in mouth opening. The immunofluorescence analysis of collagen VI in 55 biopsies from 37 patients confirmed the correlation between collagen VI defects and the severity of the clinical phenotype. However, biopsies from the same patient or from patients with the same mutation taken at different times showed a progressive increase in protein expression with age. The new finding of the time-dependent modulation of collagen VI expression should be considered in genetic correction trials

Heterobimetallic conducting polymers based on salophen complexes via electrosynthesis

In this work, we report the first electrochemical synthesis of two copolymeric bimetallic conducting polymers by a simple anodic electropolymerization method. The adopted precursors are electroactive transition metal (M = Ni, Cu and Fe) salophen complexes, which can be easily obtained by direct chemical synthesis. The resulting films, labeled poly-NiCu and poly-CuFe, were characterized by cyclic voltammetry in both organic and aqueous media, attenuated total reflectance Fourier transform infrared spectroscopy, UV-vis spectroscopy, scanning electron microscopy, and coupled energy dispersive X-ray spectroscopy. The films are conductive and exhibit great electrochemical stability in both organic and aqueous media (resistant over 100 cycles without significant loss in current response or changes in electrochemical behavior), which makes them good candidates for an array of potential applications. Electrochemical detection of ascorbic acid was performed using both materials

Scaled seismotectonic models of megathrust seismic cycles through the lens of dynamical system theory

We investigate the physics of laboratory earthquakes in scaled seismotectonic models of megathrust seismic cycles. We study models of different sizes, materials, deformation rates, and frictional configurations. We use nonlinear time-series analysis tools to characterize the dynamics of the models. Observations are described, on average, by a low-dimension (<5), similar to slow slip episodes in nature and friction experiments performed with quartz powder. Results seem insensitive to the along-strike frictional segmentation of the megathrust. Using displacement as an input variable, the instantaneous dimension and the instantaneous extremal index vary through the seismic cycles. We notice the highest values of the instantaneous dimension associated with slip phases. Under specific circumstances, clear drops of the instantaneous extremal index can serve as an early indicator of slip episodes. Prediction horizons in the order of slip duration mirror similar predictability as for slow slip episodes in nature. We conclude that seismotectonic models are effective tools to study frictional physics despite their different spatio-temporal scales

Macrophages: A minimally invasive tool for monitoring collagen VI myopathies

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