Elabela (ELA) or Toddler is a recently discovered hormone which is required for normal development of heart and vasculature through activation of apelin receptor (APJ), a G protein-coupled receptor (GPCR), in zebrafish. The present study explores whether the ELA-APJ signaling pathway is functional in the mammalian system. Using reverse-transcription PCR, we found that ELA is restrictedly expressed in human pluripotent stem cells and adult kidney whereas APJ is more widely expressed. We next studied ELA-APJ signaling pathway in reconstituted mammalian cell systems. Addition of ELA to HEK293 cells over-expressing GFP-AJP fusion protein resulted in rapid internalization of the fusion receptor. In Chinese hamster ovarian (CHO) cells over-expressing human APJ, ELA suppresses cAMP production with EC50 of 11.1 nM, stimulates ERK1/2 phosphorylation with EC50 of 14.3 nM and weakly induces intracellular calcium mobilization. Finally, we tested ELA biological function in human umbilical vascular endothelial cells and showed that ELA induces angiogenesis and relaxes mouse aortic blood vessel in a dose-dependent manner through a mechanism different from apelin. Collectively, we demonstrate that the ELA-AJP signaling pathways are functional in mammalian systems, indicating that ELA likely serves as a hormone regulating the circulation system in adulthood as well as in embryonic development.

Unique layered Ti3C2/Ni–Co–Al layered double hydroxide (LDH) heterostructures alternatively stacked with molecular-level nanosheets are for the first time synthesized by a facile liquid-phase cofeeding and electrostatic attraction heteroassemble strategy between negatively charged Ti3C2 and positively charged Ni–Co–Al-LDH nanosheets. The molecular-level Ti3C2/Ni–Co–Al-LDH heterostructures possessing the merits of both conductive and pseudocapacitive components can show greatly enhanced dynamic behavior in Faradaic reaction, which is significant for obtaining a high power density. Electrons penetrate in Ti3C2 layers, while ions diffuse rapidly along two-dimensional galleries, displaying the shortest diffusion pathway and highest efficiency for charge transfer. The Ti3C2/Ni–Co–Al-LDH heterostructure exhibits a specific capacitance of 748.2 F g–1 at current density of 1 A g–1, showing an enhanced rate capacity. Importantly, a maximum energy density of 45.8 Wh kg–1 is obtained when Ti3C2/Ni–Co–Al-LDH acts as the positive electrode for an all-solid-state flexible asymmetric supercapacitor. The results indicate that molecular-level heterotructure is a promising candidate for future high-energy supercapacitors.

Niemann-Pick disease type C (NPC) is a rare neurodegenerative disorder caused by recessive mutations in NPC1 or NPC2 gene that result in lysosomal accumulation of unesterified cholesterol in patient cells. Patient fibroblasts have been used for evaluation of compound efficacy although neuronal degeneration is the hallmark of NPC disease. Here we report the application of human NPC1 neural stem cells as a cell-based disease model to evaluate nine compounds that have been reported to be efficacious in the NPC1 fibroblasts and mouse models. These cells are differentiated from NPC1 induced pluripotent stem cells and exhibit a phenotype of lysosomal cholesterol accumulation. Treatment of these cells with hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin and δ-tocopherol significantly ameliorated the lysosomal cholesterol accumulation. Combined treatment with cyclodextrin and δ-tocopherol shows an additive/synergistic effect that otherwise requires 10-fold higher concentration of cyclodextrin alone. Additionally, we found that hydroxypropyl-β-cyclodextrin is much more potent and efficacious in the NPC1 neural stem cells, compared to the NPC1 fibroblasts. However, miglustat, SAHA, curcumin, lovastatin, pravastatin and rapamycin did not have significant effect in these cells. The results demonstrate that patient derived NPC1 neural stem cells can be used as a model system for evaluation of drug efficacy and study of disease pathogenesis.