N6-methyladenosine (m6A) is the most abundant epigenetic modification in eukaryotic mRNAs and is essential for multiple RNA processing events during mammalian development and disease control. Here we show that conditional knockout of the m6A methyltransferase Mettl3 in bone marrow mesenchymal stem cells (MSCs) induces pathological features of osteoporosis in mice. Mettl3 loss-of-function results in impaired bone formation, incompetent osteogenic differentiation potential and increased marrow adiposity. Moreover, Mettl3 overexpression in MSCs protects the mice from estrogen deficiency-induced osteoporosis. Mechanistically, we identify PTH (parathyroid hormone)/Pth1r (parathyroid hormone receptor-1) signaling axis as an important downstream pathway for m6A regulation in MSCs. Knockout of Mettl3 reduces the translation efficiency of MSCs lineage allocator Pth1r, and disrupts the PTH-induced osteogenic and adipogenic responses in vivo. Our results demonstrate the pathological outcomes of m6A mis-regulation in MSCs and unveil novel epitranscriptomic mechanism in skeletal health and diseases.

No abstract

Ionic liquids (ILs) electrolyte hold tremendous potentials to develop high‐energy‐density electric double layer capacitor due to their wide voltage windows, but are severely plagued by the sluggish mass diffusion from high viscosity and large ion size, particularly over micropore‐dominated carbon electrodes. Exploiting the carbon electrode possessing high compatibility with ILs electrolyte remains a great challenge. Herein, an emerging 3D cross‐coupled macro‐mesoporous carbon network with ultrahigh specific surface area (SSA, 2872.2 m2 g−1), N‐self doping, small‐sized mesopores (2–4 nm) and macropores (50–150 nm) is designed via a facile, versatile, and ecofriendly salt‐template strategy from the NaNO3‐gelatin biopolymer aerogel, which shows great adaptability toward high energy power density used in 4 V EMIBF4 ILs (92 Wh kg−1 is achieved at 1 kW kg−1, and notably a record high energy density of 39 Wh kg−1 is retained even at an ultrahigh power density of 200 kW kg−1). The large energy density is ascribed to the plentiful ion‐available mesoporous active sites (Smeso/SSA = 86.6%, Vmeso/Vtotal = 92.1%), while the extraordinary power density is attributed to the synergistic effects from the suitable macro‐mesoporous ion‐diffusion channels, continuous conductive network, low oxygen content (2.24%) as well as good affinity to ILs.

Conventional oligonucleotide based drug delivery systems suffer from lengthy synthetic protocols, high cost, and poor chemical or enzymatic stability under certain circumstances. Canonical free individual nucleosides cannot form stable nanostructures in aqueous solution as drug vehicles. Here, we report the development of a monomeric self-assembled nucleoside nanoparticle (SNNP) into an efficient drug delivery system which has currently no parallel in such field. This was achieved using a l-configurational pyrimido[4,5-d]pyrimidine nucleoside building block that can form robust discrete nanoparticles in just one step with water as the sole solvent. Its high biocompatibility and low toxicity was demonstrated in vitro and in vivo. In mouse xenograft model of oral squamous cell carcinoma (OSCC), SNNP loaded with 5-fluoro-uracile (5-FU-SNNP) remarkably retarded the tumor growth compared with free 5-FU, albeit SNNP alone showed no antitumor effect. The stability in blood circulation and the effective concentration of 5-FU in tumor tissue were increased upon the loading with SNNP. TUNEL and immunohistochemistry analyses further indicated that the superior in vivo antitumor efficacy of 5-FU-SNNP compared to free 5-FU was associated with an enhanced degree of inhibition of cell proliferation and stimulation of cell apoptosis. Furthermore, SNNP alleviated the toxic side effects of 5-FU. These findings suggested that when loaded with SNNP, 5-FU has better antitumor efficacy and lower side effects, indicating that SNNP can efficiently act as a readily accessible, robust, biocompatible and low-toxic nanobiomaterial which may find wide therapeutic applications clinically in the future.