The Role of Alpha-Dystrobrevin in Striated Muscle

Muscular dystrophies are a group of diseases that primarily affect striated muscle and are characterized by the progressive loss of muscle strength and integrity. Major forms of muscular dystrophies are caused by the abnormalities of the dystrophin glycoprotein complex (DGC) that plays crucial roles as a structural unit and scaffolds for signaling molecules at the sarcolemma. α-Dystrobrevin is a component of the DGC and directly associates with dystrophin. α-Dystrobrevin also binds to intermediate filaments as well as syntrophin, a modular adaptor protein thought to be involved in signaling. Although no muscular dystrophy has been associated within mutations of the α-dystrobrevin gene, emerging findings suggest potential significance of α-dystrobrevin in striated muscle. This review addresses the functional role of α-dystrobrevin in muscle as well as its possible implication for muscular dystrophy

Optical measurement of gating pore currents in hypokalemic periodic paralysis model cells

Hypokalemic periodic paralysis (HypoPP) is a rare genetic disease associated with mutations in CACNA1S or SCN4A, encoding Cav1.1 or Nav1.4, respectively. Most HypoPP-associated missense changes occur at the arginine residues within the voltage-sensing domain (VSD) of these channels. It is established that such mutations destroy the hydrophobic seal separating the external water and the internal cytosolic crevices, resulting in the generation of aberrant leak currents called gating pore currents. Presently, the gating pore currents are thought to underlie HypoPP. Here, we generated HEK293T-based HypoPP-model cell lines with the Sleeping Beauty transposon system that co-express mouse inward-rectifier potassium channel (mKir2.1) and HypoPP2-associated Nav1.4 variants. Whole cell patch-clamp measurements confirmed that mKir2.1 successfully hyperpolarized the membrane potential to comparable levels to myofibers, and that some Nav1.4 variants induced notable proton-based gating pore currents. Importantly, we succeeded in fluorometrically measuring the gating pore currents in these variants using a ratiometric pH indicator, SNARF-4F. Our optical method provides a potential in vitro platform for high-throughput drug screen, not only for HypoPP but also for other channelopathies caused by VSD mutations.Kubota T., Takahashi S., Yamamoto R., et al. Optical measurement of gating pore currents in hypokalemic periodic paralysis model cells. DMM Disease Models and Mechanisms 16, A18 (2023); https://doi.org/10.1242/dmm.049704

Using digital technologies to engage with medical research: views of myotonic dystrophy patients in Japan

As in other countries, the traditional doctor-patient relationship in the Japanese healthcare system has often been characterised as being of a paternalistic nature. However, in recent years there has been a gradual shift towards a more participatory-patient model in Japan. With advances in technology, the possibility to use digital technologies to improve patient interactions is growing and is in line with changing attitudes in the medical profession and society within Japan and elsewhere. The implementation of an online patient engagement platform is being considered by the Myotonic Dystrophy Registry of Japan. The aim of this exploratory study was to understand patients' views and attitudes to using digital tools in patient registries and engagement with medical research in Japan, prior to implementation of the digital platform.We conducted an exploratory, cross-sectional, self-completed questionnaire with a sample of myotonic dystrophy (MD) patients attending an Open Day at Osaka University, Japan. Patients were eligible for inclusion if they were 18 years or older, and were diagnosed with MD.A total of 68 patients and family members attended the Open Day and were invited to participate in the survey. Of those, 59 % submitted a completed questionnaire (n = 40). The survey showed that the majority of patients felt that they were not receiving the information they wanted from their clinicians, which included recent medical research findings and opportunities to participate in clinical trials, and 88 % of patients indicated they would be willing to engage with digital technologies to receive relevant medical information. Patients also expressed an interest in having control over when and how they received this information, as well as being informed of how their data is used and shared with other researchers.Overall, the findings from this study suggest that there is scope to develop a digital platform to engage with patients so that they can receive information about medical care and research opportunities. While this study group is a small, self-selecting population, who suffer from a particular condition, the results suggest that there are interested populations within Japan that would appreciate enhanced communication and interaction with healthcare teams

Low-temperature properties of the spin-1 antiferromagnetic Heisenberg chain with bond-alternation

We investigate the low-temperature properties of the spin-1 antiferromagnetic Heisenberg chain with bond-alternation by the quantum Monte Carlo method (loop algorithm). The strength of bond-alternation at the gapless point is estimated as $\delta_{c}=0.2595\pm0.0005$. We confirm numerically that the low-temperature properties at the gapless point are consistent with field theoretical predictions. The numerical results are compared with those of the spin-1/2 antiferromagnetic Heisenberg chain and recent experimental results for [\{Ni(333-tet)($\mu$-N$_3$)\}$_n$](ClO$_4$)$_n$ (333-tet=tetraamine $N,N^{\prime}$-bis(3-aminopropyl)-1,3-propanediamine).Comment: 18 pages, RevTex, 9 figures, Submitted to Phys.Rev.

Lambert-Eaton syndrome antibodies inhibit acetylcholine release and P/Q-type Ca2+ channels in electric ray nerve endings

The types of voltage-dependent calcium channels (VDCCs) present in the cholinergic terminals isolated from the electric organ of the ray, Narke japonica, were characterized on the basis of their pharmacological sensitivity to specific antagonists. Inhibition of these channel types by autoantibodies from patients with the Lambert-Eaton syndrome (LES) was then studied to determine the specificity of the pathogenic IgG. In normal untreated synaptosomal preparations, maximal doses of N- and P and/or Q-type Ca2+ channel antagonists, -conotoxin GVIA and -agatoxin IVA, inhibited depolarization-evoked ACh release by 47 % and 43 %, respectively. Calciseptine, an L-type VDCC antagonist, caused a 20 % reduction in the release. This indicates that the exocytotic release process is predominantly mediated by N- and P/Q-type VDCCs. LES IgG or sera caused an inhibition of ACh release by 39-45 % in comparison with the control antibody-treated preparations. The ionomycin-induced ACh release, however, was not altered by the antibodies. Additionally, the same LES antibodies inhibited whole-cell calcium currents (ICa) in bovine adrenal chromaffin cells. Thus, the pathogenic antibodies exert their action on VDCCs present in the synaptosomes. The efficacy of three Ca2+ channel antagonists in blocking ACh release was determined in preparations pretreated with LES IgG. -Agatoxin IVA produced only an additional 3-5 % reduction in release beyond that obtained with LES antibodies. Despite the pretreatment with LES IgG, -conotoxin GVIA and calciseptine inhibited the release to nearly their control levels. These results indicate that LES antibodies mainly downregulate P/Q-type Ca2+ channels which contribute to presynaptic transmitter release from the cholinergic nerve terminals of electric organ. The present findings are consistent with the hypothesis that P/Q-type VDCCs at the neuromuscular junction are the target of LES antibodies and that their inhibition by the antibodies produces the characteristic neuromuscular defect in this disease

Cantor Spectra for Double Exchange Model

We numerically study energy spectra and localization properties of the double exchange model at irrational filling factor. To obtain variational ground state, we use a mumerical technique in momentum space by ``embedded'' boundary condition which has no finite size effect a priori. Although the Hamiltonian has translation invariance, the ground state spontaneously exhibits a self-similarity. Scaling and multi-fractal analysis for the wave functions are performed and the scaling indices $\alpha$'s are obtained. The energy spectrum is found to be a singular continuous, so-called the Cantor set with zero Lebesque measure.Comment: 4 pages, 4 figures, revtex, corrected some typos, accepted for publication in PR