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Abstract Although numerous cathode materials with excellent properties have been developed for use in molten salt thermal batteries, similar progress is yet to be made with anode materials. Herein, a high-performance lithium-impregnated metal foam anode (LIMFA) is fabricated by impregnating molten lithium into a gold-coated iron–chrome–aluminium (FeCrAl) foam at 400 °C. A test cell employing the LIMFA FeCrAl anode exhibited a specific capacity of 2627 As g−1. For comparison, a cell with a conventional Li(Si) anode was also discharged, demonstrating a specific capacity of 982 As g−1. This significant improvement in performance can be attributed to the large amount (18 wt%) of lithium incorporated into the FeCrAl foam and the ability of the FeCrAl foam to absorb and immobilize molten lithium without adopting a cup system. For thermal batteries without a cup, the LIMFA FeCrAl provides the highest-reported specific capacity and a flat discharge voltage curve of molten lithium. After cell discharge, the FeCrAl foam exhibited no lithium leakage, surface damage, or structural collapse. Given these advantageous properties, in addition to its high specific capacity, LIMFA FeCrAl is expected to aid the development of thermal batteries with enhanced performance.

Abstract Background Zolgensma is a gene‐replacement therapy that has led to a promising treatment for spinal muscular atrophy (SMA). However, clinical trials of Zolgensma have raised two major concerns: insufficient therapeutic effects and adverse events. In a recent clinical trial, 30% of patients failed to achieve motor milestones despite pre‐symptomatic treatment. In addition, more than 20% of patients showed hepatotoxicity due to excessive virus dosage, even after the administration of an immunosuppressant. Here, we aimed to test whether a ubiquitination‐resistant variant of survival motor neuron (SMN), SMNK186R, has improved therapeutic effects for SMA compared with wild‐type SMN (SMNWT). Methods A severe SMA mouse model, SMA type 1.5 (Smn−/−; SMN2+/+; SMN∆7+/−) mice, was used to compare the differences in therapeutic efficacy between AAV9‐SMNWT and AAV9‐SMNK186R. All animals were injected within Postnatal Day (P) 1 through a facial vein or cerebral ventricle. Results AAV9‐SMNK186R‐treated mice showed increased lifespan, body weight, motor neuron number, muscle weight and functional improvement in motor functions as compared with AAV9‐SMNWT‐treated mice. Lifespan increased by more than 10‐fold in AAV9‐SMNK186R‐treated mice (144.8 ± 26.11 days) as compared with AAV9‐SMNWT‐treated mice (26.8 ± 1.41 days). AAV9‐SMNK186R‐treated mice showed an ascending weight pattern, unlike AAV9‐SMNWT‐treated mice, which only gained weight until P20 up to 5 g on average. Several motor function tests showed the improved therapeutic efficacy of SMNK186R. In the negative geotaxis test, AAV9‐SMNK186R‐treated mice turned their bodies in an upward direction successfully, unlike AAV9‐SMNWT‐treated mice, which failed to turn upwards from around P23. Hind limb clasping phenotype was rarely observed in AAV9‐SMNK186R‐treated mice, unlike AAV9‐SMNWT‐treated mice that showed clasping phenotype for more than 20 out of 30 s. At this point, the number of motor neurons (1.5‐fold) and the size of myofibers (2.1‐fold) were significantly increased in AAV9‐SMNK186R‐treated mice compared with AAV9‐SMNWT‐treated mice without prominent neurotoxicity. AAV9‐SMNK186R had fewer liver defects compared with AAV9‐SMNWT, as judged by increased proliferation of hepatocytes (P

Fibro-adipogenic progenitors (FAPs) are muscle-resident mesenchymal progenitors that can contribute to muscle tissue homeostasis and regeneration, as well as postnatal maturation and lifelong maintenance of the neuromuscular system. Recently, traumatic injury to the peripheral nerve was shown to activate FAPs, suggesting that FAPs can respond to nerve injury. However, questions of how FAPs can sense the anatomically distant peripheral nerve injury and whether FAPs can directly contribute to nerve regeneration remained unanswered. Here, utilizing single-cell transcriptomics and mouse models, we discovered that a subset of FAPs expressing GDNF receptors Ret and Gfra1 can respond to peripheral nerve injury by sensing GDNF secreted by Schwann cells. Upon GDNF sensing, this subset becomes activated and expresses Bdnf. FAP-specific inactivation of Bdnf (Prrx1Cre; Bdnffl/fl) resulted in delayed nerve regeneration owing to defective remyelination, indicating that GDNF-sensing FAPs play an important role in the remyelination process during peripheral nerve regeneration. In aged mice, significantly reduced Bdnf expression in FAPs was observed upon nerve injury, suggesting the clinical relevance of FAP-derived BDNF in the age-related delays in nerve regeneration. Collectively, our study revealed the previously unidentified role of FAPs in peripheral nerve regeneration, and the molecular mechanism behind FAPs’ response to peripheral nerve injury.

Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by the deficiency of the survival motor neuron (SMN) protein, which leads to motor neuron dysfunction and muscle atrophy. In addition to the requirement for SMN in motor neurons, recent studies suggest that SMN deficiency in peripheral tissues plays a key role in the pathogenesis of SMA. Using limb mesenchymal progenitor cell (MPC)-specific SMN-depleted mouse models, we reveal that SMN reduction in limb MPCs causes defects in the development of bone and neuromuscular junction (NMJ). Specifically, these mice exhibited impaired growth plate homeostasis and reduced insulin-like growth factor (IGF) signaling from chondrocytes, rather than from the liver. Furthermore, the reduction of SMN in fibro-adipogenic progenitors (FAPs) resulted in abnormal NMJ maturation, altered release of neurotransmitters, and NMJ morphological defects. Transplantation of healthy FAPs rescued the morphological deterioration. Our findings highlight the significance of mesenchymal SMN in neuromusculoskeletal pathogenesis of SMA and provide insights into potential therapeutic strategies targeting mesenchymal cells for the treatment of SMA.

Abstract Background With organismal aging, the hypothalamic–pituitary–gonadal (HPG) activity gradually decreases, resulting in the systemic functional declines of the target tissues including skeletal muscles. Although the HPG axis plays an important role in health span, how the HPG axis systemically prevents functional aging is largely unknown. Methods We generated muscle stem cell (MuSC)‐specific androgen receptor (Ar) and oestrogen receptor 2 (Esr2) double knockout (dKO) mice and pharmacologically inhibited (Antide) the HPG axis to mimic decreased serum levels of sex steroid hormones in aged mice. After short‐term and long‐term sex hormone signalling ablation, the MuSCs were functionally analysed, and their aging phenotypes were compared with those of geriatric mice (30‐month‐old). To investigate pathways associated with sex hormone signalling disruption, RNA sequencing and bioinformatic analyses were performed. Results Disrupting the HPG axis results in impaired muscle regeneration [wild‐type (WT) vs. dKO, P

Muscle atrophy is associated with ageing, but the underlying molecular mechanisms are not well understood. Here, they authors show that ablation of the E3 ubiquitin ligase Mib1 is important for myofibre maintenance via a mechanism that involves targeting and degradation of Actn3, and that Mib1 ablation in mice induces muscle atrophy which can be rescued by knockown of Actn3 expression.

The survival of motor neuron (SMN) protein is a major component of the pre-mRNA splicing machinery and is required for RNA metabolism. Although SMN has been considered a fundamental gene for the central nervous system, due to its relationship with neuromuscular diseases, such as spinal muscular atrophy, recent studies have also revealed the requirement of SMN in non-neuronal cells in the peripheral regions. Here, we report that the fibro-adipogenic progenitor subpopulation expressing Dpp4 (Dpp4+ FAPs) is required for the neuromuscular system. Furthermore, we also reveal that BRCA1-associated protein-1 (Bap1) is crucial for the stabilization of SMN in FAPs by preventing its ubiquitination-dependent degradation. Inactivation of Bap1 in FAPs decreased SMN levels and accompanied degeneration of the neuromuscular junction, leading to loss of motor neurons and muscle atrophy. Overexpression of the ubiquitination-resistant SMN variant, SMNK186R, in Bap1-null FAPs completely prevented neuromuscular degeneration. In addition, transplantation of Dpp4+ FAPs, but not Dpp4– FAPs, completely rescued neuromuscular defects. Our data reveal the crucial role of Bap1-mediated SMN stabilization in Dpp4+ FAPs for the neuromuscular system and provide the possibility of cell-based therapeutics to treat neuromuscular diseases.

The inclusion, the intersection and the union between cubic sets are each defined in two ways. From this point of view, we introduce the concepts of cubic subgroupoids, cubic ideals, cubic subgroups, and cubic congruences as two types, respectively, and discuss their various properties. In particular, we give a relationship between the set of all cubic normal subgroups of a group and all cubic congruences on the group.