Opposing roles of miR-21 and miR-29 in the progression of fibrosis in Duchenne muscular dystrophy

AbstractExcessive extracellular matrix deposition progressively replacing muscle fibres is the endpoint of most severe muscle diseases. Recent data indicate major involvement of microRNAs in regulating pro- and anti-fibrotic genes. To investigate the roles of miR-21 and miR-29 in muscle fibrosis in Duchenne muscle dystrophy, we evaluated their expression in muscle biopsies from 14 patients, and in muscle-derived fibroblasts and myoblasts. In Duchenne muscle biopsies, miR-21 expression was significantly increased, and correlated directly with COL1A1 and COL6A1 transcript levels. MiR-21 expression was also significantly increased in Duchenne fibroblasts, more so after TGF-β1 treatment. In Duchenne fibroblasts the expression of miR-21 target transcripts PTEN (phosphatase and tensin homolog deleted on chromosome 10) and SPRY-1 (Sprouty homolog 1) was significantly reduced; while collagen I and VI transcript levels and soluble collagen production were significantly increased. MiR-29a and miR-29c were significantly reduced in Duchenne muscle and myoblasts, and miR-29 target transcripts, COL3A1, FBN1 and YY1, significantly increased. MiR-21 silencing in mdx mice reduced fibrosis in the diaphragm muscle and in both Duchenne fibroblasts and mdx mice restored PTEN and SPRY-1 expression, and significantly reduced collagen I and VI expression; while miR-29 mimicking in Duchenne myoblasts significantly decreased miR-29 target transcripts. These findings indicate that miR-21 and miR-29 play opposing roles in Duchenne muscle fibrosis and suggest that pharmacological modulation of their expression has therapeutic potential for reducing fibrosis in this condition

A novel mutation in the N-terminal acting-binding domain of Filamin C protein causing a distal myofibrillar myopathy

Variants in Filamin C (FLNC) gene may cause either cardiomyopathies or different myopathies. We describe a family affected by a distal myopathy with autosomal dominant inheritance. The onset of the disease was in the third decade with gait impairment due to distal leg weakness. Subsequently, the disease progressed with an involvement of proximal lower limbs and hand muscles. Muscle biopsy, performed in one subject,identified relevant myofibrillar abnormalities. We performed a target gene panel testing for myofibrillar myopathies by NGS approach which identified a novel mutation in exon 3 of FLNC gene (c.A664G:p.M222V), within the N-terminal actin-binding (ABD) domain. This variant has been identified in all affected members of the family, thus supporting its pathogenic role. Differently from previously identified variants, our family showed a predominant leg involvement and myofibrillar aggregates, thus further expanding the spectrum of Filamin C related myopathies

Dysfunction of voltage-gated K + Channels Kv1.1 in sciatic nerve causes spontaneous and stress-induced neuromuscular hyperexcitability

Episodic ataxia type 1 (EA1) is an autosomal dominant neurological disorder characterized by myokymia and attacks of ataxic gait precipitated by stress events. Several genetic mutations have been identified in the Shaker-like K+ channel Kv1.1 (KCNA1) of EA1 individuals, including the V408A which results in remarkable channel dysfunction. By inserting heterozygous V408A mutation in one Kv1.1 allele, a mouse model of EA1 has been generated (Kv1.1 V408A/+). Here, we hypothesized that dysfunction of Kv1.1 channels in sciatic nerve of Kv1.1V408A/+ ataxia mice leads to neuromuscular hyperexcitability and to abnormal susceptibility to different stressors. By using in vivo preparations of lateral gastrocnemius (LG) nerve–muscle from Kv1.1+/+ and Kv1.1V408A/+ mice, we show that the mutant animals exhibit spontaneous myokymic discharges consisting of repeated singlets, duplets or multiplets, despite sciatic nerve axotomy. Two-photon laser scanning microscopy from the sciatic nerve, ex vivo, revealed spontaneous Ca2+ signals that occurred abnormally only in preparations dissected from Kv1.1V408A/+ mice. The spontaneous bursting activity, as well as that evoked by motor nerve stimulation, was exacerbated by muscle fatigue, ischemia and low temperatures. These stressors also increased the amplitude of muscle compound action potential. Such abnormal neuromuscular transmission did not alter fiber type composition neuromuscular junction and vascularization of LG muscle analyzed by light and electron microscopy. These findings indicate that dysfunction of Kv1.1 channels results in sciatic nerve hyperexcitability and myokymia/neuromyotonia in Kv1.1V408A/+ ataxia mice. Moreover, this study sheds new light on the functional role played by K + channels segregated under the myelin sheath, which becomes crucial in certain situations of physiological stress.peer-reviewe

Electrodeposition of cobalt thin films and nanowires from ethylene glycol-based solution

Ethylene glycol-based solutions containing metal precursor chloride salts were investigated for the electrodeposition of cobalt thin films and nanowires. The electrochemical behavior of 0.5 M Co(II) chloride solution at 70 °C was studied by means of cyclic voltammetry (CV) on a Pt substrate. The reduction process was shown to be irreversible, with high faradaic efficiencies (85–90 %). A diffusion coefficient (D0) of 2.29 × 10−6 cm2 s−1 for the Co species was estimated from the electrochemical behavior at different scan rates (from 25 to 125 mV s−1). The electrodeposition process was also studied on a copper substrate at different cathodic potentials (from −0.75 V vs Pt to −0.95 V vs Pt). Field-emission scanning electron microscopy (FE-SEM) and electron dispersive spectroscopy (EDS) revealed high-purity, compact films. Template-assisted electrodeposition resulted in ~16–18 μm long cobalt nanowires with an aspect ratio L/D > 100. X-ray diffraction (XRD) analysis of Co thin films showed a preferential orientation along the HCP [100] direction, which was even more marked for the nanowires. Vibrating sample magnetometry (VSM) highlighted that the fact that Co thin films were magnetized in-plane, while in nanowires a competition between shape and magnetocrystalline anisotropy led to similar magnetic behavior for the in-plane and out-of-plane directions

Late onset of neutral lipid storage disease due to novel PNPLA2 mutations causing total loss of lipase activity in a patient with myopathy and slight cardiac involvement

Neutral lipid storage disease with myopathy (NLSDM) presents with skeletal muscle myopathy and severe dilated cardiomyopathy in nearly 40% of cases. NLSDM is caused by mutations in the PNPLA2 gene, which encodes the adipose triglyceride lipase (ATGL). Here we report clinical and genetic findings of a patient carrying two novel PNPLA2 mutations (c.696+4A>G and c.553_565delGTCCCCCTTCTCG). She presented at age 39 with right upper limb abduction weakness slowly progressing over the years with asymmetric involvement of proximal upper and lower limb muscles. Cardiological evaluation through ECG and heart echo scan was normal until the age 53, when mild left ventricular diastolic dysfunction was detected. Molecular analysis revealed that only one type of PNPLA2 transcript, with exon 5 skipping, was expressed in patient cells. Such aberrant mRNA causes the production of a shorter ATGL protein, lacking part of the catalytic domain. This is an intriguing case, displaying severe PNPLA2 mutations with clinical presentation characterized by slight cardiac impairment and full expression of severe asymmetric myopathy

Quasi 1D Electronic Transport in a 2D Magnetic Semiconductor

We investigate electronic transport through exfoliated multilayers of CrSBr, a 2D semiconductor that is attracting attention because of its magnetic properties. We find an extremely pronounced anisotropy that manifests itself in qualitative and quantitative differences of all quantities measured along the in-plane \textit{a} and \textit{b} crystallographic directions. In particular, we observe a qualitatively different dependence of the conductivities $\sigma_a$ and $\sigma_b$ on temperature and gate voltage, accompanied by orders of magnitude differences in their values ($\sigma_b$/$\sigma_a \approx 3\cdot10^2-10^5$ at low temperature and large negative gate voltage). We also find a different behavior of the longitudinal magnetoresistance in the two directions, and the complete absence of the Hall effect in transverse resistance measurements. These observations appear not to be compatible with a description in terms of conventional band transport of a 2D doped semiconductor. The observed phenomenology --together with unambiguous signatures of a 1D van Hove singularity that we detect in energy resolved photocurrent measurements-- indicate that electronic transport through CrSBr multilayers is better interpreted by considering the system as formed by weakly and incoherently coupled 1D wires, than by conventional 2D band transport. We conclude that CrSBr is the first 2D semiconductor to show distinctly quasi 1D electronic transport properties

Influence of magnetism on vertical hopping transport in CrSBr

Data set for: Physical Review Research (2024) https://doi.org

Quasi 1D Electronic Transport in a 2D Magnetic Semiconductor

AbstractData set for: Advanced Materials 2109759 (2022

Varia

Ce numéro 21 de « Varia » (selon la formule bisannuelle de la revue) réunit des contributions originales de jeunes chercheurs (articles et dossier central), ainsi que des comptes rendus de lecture. C’est un numéro placé assez largement sous le signe de Pétrarque. En effet, deux des quatre articles de la première section sont consacrés au poète de Laure et à sa réception française. Le dossier, quant à lui, propose un point extrêmement utile sur le recueil mal connu des Epystole, paradoxalement négligé alors qu’il s’agit d’un véritable ‘livre d’auteur’, l’un des rares qui aient été ‘publiés’ par celui-ci. Les deux autres études de la première partie concernent, pour l’un, une ‘joute poétique’ dissimulée entre deux auteurs (Guido Novello da Polenta – si c’est bien de lui qu’il s’agit – et Cecco d’Ascoli) qui ont à l’égard de Dante des attitudes diamétralement opposées ; pour l’autre, une subtile analyse des liens entre extériorité et intériorité dans l’Elegia di madonna Fiammetta de Boccace. Les comptes rendus, quant à eux, entendent signaler à l'attention de la communauté scientifique des parutions encore récentes qui nous ont paru particulièrement importantes. D’autres auraient sans aucun doute mérité d’y figurer, mais l’exhaustivité était hors de portée. Nous tâcherons de réparer, au moins pour partie, avec le prochain numéro de « Varia » (23)