The protective effects of MSC‐EXO against pulmonary hypertension through regulating Wnt5a/BMP signalling pathway

The aim of the study was to explore the mechanism of mesenchymal stem cell‐derived exosomes (MSC‐EXO) to protect against experimentally induced pulmonary hypertension (PH). Monocrotaline (MCT)‐induced rat model of PH was successfully established by a single intraperitoneal injection of 50 mg/kg MCT, 3 weeks later the animals were treated with MSC‐EXO via tail vein injection. Post‐operation, our results showed that MSC‐EXO could significantly reduce right ventricular systolic pressure (RVSP) and the right ventricular hypertrophy index, attenuate pulmonary vascular remodelling and lung fibrosis in vivo. In vitro experiment, the hypoxia models of pulmonary artery endothelial cell (PAEC) and pulmonary vascular smooth muscle cell (PASMC) were used. We found that the expression levels of Wnt5a, Wnt11, BMPR2, BMP4 and BMP9 were increased, but β‐catenin, cyclin D1 and TGF‐β1 were decreased in MSC‐EXO group as compared with MCT or hypoxia group in vivo or vitro. However, these increased could be blocked when cells were transfected with Wnt5a siRNA in vitro. Taken together, these results suggested that the mechanism of MSC‐EXO to prevent PH vascular remodelling may be via regulation of Wnt5a/BMP signalling pathway.     

Clinical Utility of Insulin-Like Growth Factor 1 and 2; Determination by High Resolution Mass Spectrometry

Measurement of insulin-like growth factor-1 (IGF-I) has utility for the diagnosis and management of growth disorders, but inter-assay comparison of results has been complicated by a multitude of reference standards, antibodies, detection methods, and pre-analytical preparation strategies. We developed a quantitative LC-MS method for intact IGF-I, which has advantages in throughput and complexity when compared to mass spectrometric approaches that rely on stable isotope dilution analysis of tryptic peptides. Since the method makes use of full-scan data, the assay was easily extended to provide quantitative measurement of IGF-II using the same assay protocol. The validated LC-MS assay for IGF-I and IGF-II provides accurate results across the pediatric and adult reference range and is suitable for clinical use.     

The evolution of Nyctereutes (Carnivora: Canidae) in the Nihewan Basin,Hebei, northern China

The occurrence of Nyctereutes during the Plio-Pleistocene has long been reported in northern China, with the highest abundance in the Nihewan Basin. However, due to site dispersal, the coexistence of different taxa, and lack of a precise stratigraphic constraint, the evolutionary process of this genus remains enigmatic. In this study, we re-examined the available Nyctereutes materials recovered from the Nihewan Basin housed in IVPP and Tianjin Natural History Museum, in addition to a newly recovered specimen from our latest excavation. Furthermore, we compared these materials with Nyctereutes fossils recovered from the Pleistocene Zhoukoudian sites near Beijing and the extant species N. procyonoides. Our analysis of the upper molar morphometry reveals the variations in size and dietary characteristics within different species of Nyctereutes during the late Plio-Pleistocene. The examination of molars indicates an increase in the size of Nyctereutes sinensis compared to early Pliocene N. tingi as well as changes in the molar teeth morphology. Subsequently, changes in diet or environmental factors possibly caused the decrease of body size in the late Pleistocene. We also estimate an age constraint for the fossils of N. sinensis from the Xiashagou section by relocating Licent's localities and referring of updated magnetostratigraphic data.     

Structural Differences between Aβ(1-40) Intermediate Oligomers and Fibrils Elucidated by Proteolytic Fragmentation and Hydrogen/Deuterium Exchange

The aggregation of amyloid-β protein (Aβ) in vivo is a critical pathological event in Alzheimer's disease. Although more and more evidence shows that the intermediate oligomers are the primary neurotoxic species in Alzheimer's disease, the particular structural features responsible for the toxicity of these intermediates are poorly understood. We measured the peptide level solvent accessibility of multiple Aβ(1-40) aggregated states using hydrogen exchange detected by mass spectrometry. A gradual reduction in solvent accessibility, spreading from the C-terminal region to the N-terminal region was observed with ever more aggregated states of Aβ peptide. The observed hydrogen exchange protection begins with reporter peptides 20-34 and 35-40 in low molecular weight oligomers found in fresh samples and culminates with increasing solvent protection of reporter peptide 1-16 in long time aged fibrillar species. The more solvent exposed structure of intermediate oligomers in the N-termini relative to well-developed fibrils provides a novel explanation for the structure-dependent neurotoxicity of soluble oligomers reported previously.     

Demonstration of choleragen-dependent ADP-ribosylation in whole cells and correlation with the activation of adenylate cyclase

3T3C₂ mouse fibroblasts rendered permeable to (α^?32P)NAD⁺ show cholera toxin-dependent labeling of a 45,000 m.w. protein and of a doublet of polypeptides around 52,000 m.w. These same bands are ADP-ribosylated in broken cells. Membranes prepared from pigeon erythrocytes pretreated with choleragen show a decrease in subsequent cholera toxin-specific ADP-ribosylation of a 43,000 m.w. polypeptide. Both whole cell and broken cell adenylate cyclase activation and toxin-specific ADP-ribosylation are reversed specifically by low pH and high concentrations of toxin and nicotinamide in all systems. Thus ADP-ribosylation appears to be relevant to the molecular action of choleragen in whole cells as well as in broken cells.