Filamentous tangles with nemaline rods in MYH2 myopathy: a novel phenotype

The MYH2 gene encodes the skeletal muscle myosin heavy chain IIA (MyHC-IIA) isoform, which is expressed in the fast twitch type 2A fibers. Autosomal dominant or recessive pathogenic variants in MYH2 lead to congenital myopathy clinically featured by ophthalmoparesis and predominantly proximal weakness. MYH2-myopathy is pathologically characterized by loss and atrophy of type 2A fibers. Additional myopathological abnormalities have included rimmed vacuoles containing small p62 positive inclusions, 15–20 nm tubulofilaments, minicores and dystrophic changes. We report an adult patient with late-pediatric onset MYH2-myopathy caused by two heterozygous pathogenic variants: c.3331C>T, p.Gln1111* predicted to result in truncation of the proximal tail region of MyHC-IIA, and c.1546T>G, p.Phe516Val, affecting a highly conserved amino acid within the highly conserved catalytic motor head relay loop. This missense variant is predicted to result in a less compact loop domain and in turn could affect the protein affinity state. The patient’s genotype is accompanied by a novel myopathological phenotype characterized by centralized large myofilamentous tangles associated with clusters of nemaline rods, and ring fibers, in addition to the previously reported rimmed vacuoles, paucity and atrophy of type 2A fibers. Electron microscopy demonstrated wide areas of disorganized myofibrils which were oriented in various planes of direction and entrapped multiple nemaline rods, as corresponding to the large tangles with rods seen on light microscopy. Nemaline rods were rarely observed also in nuclei. We speculate that the mutated MyHC-IIA may influence myofibril disorganization. While nemaline rods have been described in myopathies caused by pathogenic variants in genes encoding several sarcomeric proteins, to our knowledge, nemaline rods have not been previously described in MYH2-myopathy.

A Heterozygous Mutation in the Filamin C Gene Causes an Unusual Nemaline Myopathy With Ring Fibers

Autosomal dominant pathogenic variants in the filamin C gene (FLNC) have been associated with myofibrillar myopathies, distal myopathies, and isolated cardiomyopathies. Mutations in different functional domains of FLNC can cause various clinical phenotypes. A novel heterozygous missense variant c.608G>A, p.(Cys203Tyr) in the actin binding domain of FLCN was found to cause an upper limb distal myopathy (MIM #614065). The muscle MRI findings are similar to those observed in FLNC-myofibrillar myopathy (MIM #609524). However, the muscle biopsy revealed >20% of muscle fibers with nemaline bodies, in addition to numerous ring fibers and a predominance of type 1 fibers. Overall, this case shows some unique and rare aspects of FLNC-myopathy constituting a new morphologic phenotype of FLNC-related myopathies.

CAP2 deficiency delays myofibril actin cytoskeleton differentiation and disturbs skeletal muscle architecture and function

Actin filaments (F-actin) are key components of sarcomeres, the basic contractile units of skeletal muscle myofibrils. A crucial step during myofibril differentiation is the sequential exchange of α-actin isoforms from smooth muscle (α-SMA) and cardiac (α-CAA) to skeletal muscle α-actin (α-SKA) that, in mice, occurs during early postnatal life. This “α-actin switch” requires the coordinated activity of actin regulators because it is vital that sarcomere structure and function are maintained during differentiation. The molecular machinery that controls the α-actin switch, however, remains enigmatic. Cyclase-associated proteins (CAP) are a family of actin regulators with largely unknown physiological functions. We here report a function for CAP2 in regulating the α-actin exchange during myofibril differentiation. This α-actin switch was delayed in systemic CAP2 mutant mice, and myofibrils remained in an undifferentiated stage at the onset of the often excessive voluntary movements in postnatal mice. The delay in the α-actin switch coincided with the onset of motor function deficits and histopathological changes including a high frequency of type IIB ring fibers. Our data suggest that subtle disturbances of postnatal F-actin remodeling are sufficient for predisposing muscle fibers to form ring fibers. Cofilin2, a putative CAP2 interaction partner, has been recently implicated in myofibril actin cytoskeleton differentiation, and the myopathies in cofilin2 and CAP2 mutant mice showed striking similarities. We therefore propose a model in which CAP2 and cofilin2 cooperate in actin regulation during myofibril differentiation.

ANALYSIS OF DEFORMATIONS OF AN ELASTOPROPED TUBE UNDER THE INFLUENCE OF INTERNAL PRESSURE

The study of the deformation of soft composite structures, when their initial configuration changes significantly, re-mains one of the problems of the mechanics of composite materials. As one of these structures, we considered a long thin-walled tube of elastic layers with ring fibers of a more rigid elastic material. Pipes of this structure can be used to create flexible gas and air ducts, in order to transport substances in a spray form, to collect environmentally hazardous waste. The most common approach in the study of the bodies of a fibrous structure is based on the use of a model of a piecewise-homogeneous medium, when the matrix and fibers are considered as contacting bodies. A numerical solution of the problem according to this model of the deformation of a pipe of three layers with circular fibers of square cross section under the influence of internal pressure during large displacements and deformations is presented. The pipe was modeled as an assembly of ring elements. Such elements are square rings of a binder material, including ring fibers as their reinforcing core. The pipe design was accepted as a long cylindrical shell, which is axisymmetrically deformable under pressure, when the extreme and central sections of the ring elements move in the planes of their initial position. The boundary problem for assembling the ring elements of the shell was formulated on the basis of the equations of the nonlinear theory of elasticity for the matrix and the fibers in it. The problem was solved using the finite difference method, the first order derivatives of the main quantities with respect to the axial and radial coordinates were approximated using second-order finite-difference relations. The discrete analogue of the problem was solved on the basis of the Newton method procedure. The uniqueness of the solution of the boundary value problem was ensured by the continuation of the pressure solution in the pipe.

Radiocarbon Measurements of Paper: A Forensic Case Study to Determine the Absolute Age of Paper in Documents and Works of Art

ABSTRACTIn a case study to assess the possibilities and limitations of determining the exact age of paper, we measured radiocarbon (14C) concentrations in bulk-paper cellulose and starch extracts from 20 known-age paper samples of the last 65 yr. As expected, 14C concentrations in single-seasonal grown starch extracts are in reasonably good agreement with post-bomb atmospheric 14C. In contrast, 14C concentrations in bulk-paper cellulose indicate apparent admixtures of tree-ring fibers spanning up to >50 yr. In a forensic investigation, combining 14C results from single-seasonal components like starch with those from long-lived fibers, could potentially enhance the precision of paper production-date estimates for samples made after 1955.