Disrupting CD147-RAP2 interaction abrogates erythrocyte invasion by Plasmodium falciparum.

Effective vaccines against malaria caused by Plasmodium falciparum are still lacking, and the molecular mechanism of the host-parasite interaction is not fully understood. Here we demonstrate that the interaction of RAP2, a parasite-secreted rhoptry protein that functions in the parasitophorous vacuole formation stage of the invasion, and CD147 on the host erythrocyte is essential for erythrocyte invasion by P falciparum and is independent from all previously identified interactions involved. Importantly, the blockade of the CD147-RAP2 interaction by HP6H8, a humanized CD147 antibody, completely abolished the parasite invasion with both cure and preventative functions in a humanized mouse model. Together with its long half-life on human red blood cells and its safety profile in cynomolgus monkeys, HP6H8 is the first antibody that offers an advantageous approach by targeting a more conserved late-stage parasite ligand for preventing as well as treating severe malaria.

Loneliness, Stress, and Depressive Symptoms Among the Chinese Rural Empty Nest Elderly: A Moderated Mediation Analysis.

This study aimed to explore the relationship of loneliness, perceived stress, and depressive symptoms among the Chinese rural empty nest elderly. The role of sense of coherence (SOC) as a moderating variable was investigated in a representative sample of older adults in Henan, China, from November 2016 to February 2017. Results indicated that perceived stress mediated the relationship between loneliness and depressive symptoms, and SOC acted as a moderator on this mediating model. The mediation effect of perceived stress was significant only when SOC was lower. The results emphasized the importance of perceived stress in older adults. SOC was a protective factor with regard to depressive symptoms, and improving SOC should be a focus of health promotion with the elderly.

Locomotive function and quality of life among older people in Liaoning, China: Falls efficacy as mediator or moderator?

OBJECTIVES: This study aimed to examine the role of falls efficacy in the relationship between the locomotive function and quality of life. METHODS: From March to May in 2016, we conducted a cross-sectional survey among 830 community residents aged ≥60 years from Jinzhou,China.GLFS-25 (25-question Geriatric Locomotive Function Scale), FES-I(International edition of Falls Efficacy Scale),and SF-12 (12-item Short Form Health Survey) were used to estimate locomotive function, falls efficacy and quality of life, respectively. The higher score of GLFS-25, the worse the locomotive function. RESULTS: Median age was 68.69 years (ranges 60-88). Locomotive function, falls efficacy and quality of life all presented a linear relationship within each other, locomotive function score was negatively correlated with falls efficacy score (-0.461, P < 0.01). locomotive function score was negatively correlated with quality of life score (-0.523, P < 0.01).Falls efficacy score was positively correlated with quality of life score (0.415, P < 0.01).Falls efficacy exerted both a mediating and moderating role between locomotive function and quality of life, and the mediation effect accounted for 45.5% of the total effect. CONCLUSIONS: Poorer locomotive function was associated with poorer quality of life, and greater falls efficacy was associated with better quality of life. In addition, falls efficacy was demonstrated to be both a mediator and moderator variable in the linkage between locomotive function and quality of life. Aged care professional practitioners and our policy makers should strengthen the awareness of the psychological role of the elderly falls efficacy.

Effects of metabolic uncouplers on excess sludge reduction and microbial products of activated sludge.

The present study investigated the influences of three metabolic uncouplers (pCP, oCP and oNP) on excess activated sludge reduction and microbial products of extracellular polymeric substances (EPS) and intracellular storage product (polyhydroxybutyrate, PHB) in short-term tests. Results showed sludge was reduced 58.2%, 59.8% and 80.8%, respectively, at pCP, oCP and oNP concentrations of 20mg/L. The dosage of three uncouplers had no obviously influences on COD removal and sludge settleability, but had significant inhibition effect on ammonia removal, especially for oNP. Low concentration of pCP and oNP (5mg/L) dosing resulted in protein and polysaccharide content increased in EPS, however, they were decreased at high pCP and oNP concentrations (>5mg/L). To oCP, the protein content in EPS was increased linearly with oCP concentration. Furthermore, metabolic uncouplers addition stimulated the production of PHB. Among three uncouplers, oCP could be an alternative uncoupler for sludge reduction in activated sludge process.

Blockade of nonhormonal fibroblast growth factors by FP-1039 inhibits growth of multiple types of cancer.

The fibroblast growth factor (FGF) pathway promotes tumor growth and angiogenesis in many solid tumors. Although there has long been interest in FGF pathway inhibitors, development has been complicated: An effective FGF inhibitor must block the activity of multiple mitogenic FGF ligands but must spare the metabolic hormone FGFs (FGF-19, FGF-21, and FGF-23) to avoid unacceptable toxicity. To achieve these design requirements, we engineered a soluble FGF receptor 1 Fc fusion protein, FP-1039. FP-1039 binds tightly to all of the mitogenic FGF ligands, inhibits FGF-stimulated cell proliferation in vitro, blocks FGF- and vascular endothelial growth factor (VEGF)-induced angiogenesis in vivo, and inhibits in vivo growth of a broad range of tumor types. FP-1039 antitumor response is positively correlated with RNA levels of FGF2, FGF18, FGFR1c, FGFR3c, and ETV4; models with genetic aberrations in the FGF pathway, including FGFR1-amplified lung cancer and FGFR2-mutated endometrial cancer, are particularly sensitive to FP-1039-mediated tumor inhibition. FP-1039 does not appreciably bind the hormonal FGFs, because these ligands require a cell surface co-receptor, klotho or ß-klotho, for high-affinity binding and signaling. Serum calcium and phosphate levels, which are regulated by FGF-23, are not altered by administration of FP-1039. By selectively blocking nonhormonal FGFs, FP-1039 treatment confers antitumor efficacy without the toxicities associated with other FGF pathway inhibitors.

Discovery of a cytokine and its receptor by functional screening of the extracellular proteome.

To understand the system of secreted proteins and receptors involved in cell-cell signaling, we produced a comprehensive set of recombinant secreted proteins and the extracellular domains of transmembrane proteins, which constitute most of the protein components of the extracellular space. Each protein was tested in a suite of assays that measured metabolic, growth, or transcriptional responses in diverse cell types. The pattern of responses across assays was analyzed for the degree of functional selectivity of each protein. One of the highly selective proteins was a previously undescribed ligand, designated interleukin-34 (IL-34), which stimulates monocyte viability but does not affect responses in a wide spectrum of other assays. In a separate functional screen, we used a collection of extracellular domains of transmembrane proteins to discover the receptor for IL-34, which was a known cytokine receptor, colony-stimulating factor 1 (also called macrophage colony-stimulating factor) receptor. This systematic approach is thus useful for discovering new ligands and receptors and assessing the functional selectivity of extracellular regulatory proteins.

Lipoprotein receptor binding, cellular uptake, and lysosomal delivery of fusions between the receptor-associated protein (RAP) and alpha-L-iduronidase or acid alpha-glucosidase.

Enzyme replacement therapy for lysosomal storage disorders depends on efficient uptake of recombinant enzyme into the tissues of patients. This uptake is mediated by oligosaccharide receptors including the cation-independent mannose 6-phosphate receptor and the mannose receptor. We have sought to exploit alternative receptor systems that are independent of glycosylation but allow for efficient delivery to the lysosome. Fusions of the human lysosomal enzymes alpha-l-iduronidase or acid alpha-glucosidase with the receptor-associated protein were efficiently endocytosed by lysosomal storage disorder patient fibroblasts, rat C6 glioma cells, mouse C2C12 myoblasts, and recombinant Chinese hamster ovary cells expressing individual members of the low-density lipoprotein receptor family. Uptake of the fusions exceeded that of phosphorylated enzyme in all cases, often by an order of magnitude or greater. Uptake was specifically mediated by members of the low-density lipoprotein receptor protein family and was followed by delivery of the fusions to the lysosome. The advantages of the lipoprotein receptor system over oligosaccharide receptor systems include more efficient cellular delivery and the potential for transcytosis of ligands across tight endothelia, including the blood-brain barrier.