Arterial medial calcification (AMC) is prevalent in patients with chronic kidney disease (CKD) and contributes to elevated risk of cardiovascular events and mortality. Vascular smooth muscle cells (VSMCs) to osteogenic transdifferentiation (VOT) in a high-phosphate environment is involved in the pathogenesis of AMC in CKD. WNT/β-catenin signaling is indicated to play a crucial role in osteogenesis via promoting Runx2 expression in osteoprogenitor cells, however, its role in Runx2 regulation and VOT remains incompletely clarified. In this study, Runx2 was induced and β-catenin was activated by high-phosphate in VSMCs. Two forms of active β-catenin, dephosphorylated on Ser37/Thr41 and phosphorylated on Ser675 sites, were upregulated by high-phosphate. Activation of β-catenin, through ectopic expression of stabilized β-catenin, inhibition of GSK-3β, or WNT-3A protein, induced Runx2 expression, whereas blockade of WNT/β-catenin signaling with Porcupine (PORCN) inhibitor or Dickkopf-1 (DKK1) protein inhibited Runx2 induction by high-phosphate. WNT-3A promoted osteocalcin expression and calcium deposition in VSMCs, whereas DKK1 ameliorated calcification of VSMCs induced by high-phosphate. Two functional T cell factor (TCF)/lymphoid enhancer-binding factor binding sites were identified in the promoter region of Runx2 gene in VSMCs, which interacted with TCF upon β-catenin activation. Site-directed mutation of each of them attenuated Runx2 response to β-catenin, and deletion or destruction of both of them completely abolished this responsiveness. In the aortic tunica media of rats with chronic renal failure, followed by AMC, Runx2 and β-catenin was induced, and the Runx2 mRNA level was positively associated with the abundance of phosphorylated β-catenin (Ser675). Collectively, our study suggested that high-phosphate may activate WNT/β-catenin signaling through different pathways, and the activated WNT/β-catenin signaling, through direct downstream target Runx2, could play an important role in promoting VOT and AMC.

1 The agonist activities of a range of prostaglandin analogues on smooth muscle preparations sensitive to prostaglandin E2 (PGE2) have been investigated. When necessary thromboxane-like activity was eliminated using the thromboxane receptor antagonists EP 045 and EP 092. 2 On the bullock iris sphincter, rat stomach fundus and guinea-pig trachea, (±) w-tetranor-16-pchlorophenoxy PGE2 (ICI 80205) and 16,16-dimethyl PGE2 were more active contractile agents than PGE2, whereas for relaxant activity on the cat trachea, guinea-pig trachea and dog hind limb arterial vessels in vivo the order of potency was reversed. 1I -Deoxy PGEI exhibited greater relaxant than contractile activity when compared to PGE2.3 Iloprost and 6a-carba-A6,6aPGII (potent mimetics of PGI2) showed high contractile activity on the PGE-sensitive preparations. PG12 was less active and another potent PGI2 mimetic, ZK 96480, showed only very weak activity. When tested, the dibenzoxazepines SC 19220 and SC 25191 blocked the contractile actions of iloprost and 6a-carba-A6,'PGI, and those of PGE2 and 16,16-dimethyl PGE2 to similar extents. Each of the PG12 analogues showed weak activity on the relaxant systems.4 On the proximal portion of the ascending colon of the rat, PGI2, iloprost, 6a-carba-A6'IPGII and ZK 96480 always inhibited spontaneous activity at nanomolar concentrations. PGE2 and PGE, showed weak contractile activity. The distal portion of the ascending colon was more responsive to the contractile action of PGE analogues: both iloprost and 6a-carba-A6',PGI, showed evidence of contractile activity, whereas PGI2 and ZK 96480 always inhibited spontaneous activity. 5 Evidence was obtained that the rat stomach fundus also contains a PGF receptor; (± ) w-tetranor-16-m-trifluoromethylphenoxy PGF2A (ICI 81008) acted as a specific agonist. PGF2, and its w-tetranor-16-p-fluorophenoxy analogue produced a higher maximum response that ICI 81008 probably due to their additional agonist action at the PGE receptor. 6 The data support the hypothesis that there are two subtypes of the PGE receptor. ZK 96480 has minimal activity on both receptor subtypes and appears to be a highly specific PGI2 mimetic.

[1] Using a large amount of aircraft measurements of cloud droplet size distributions, the relationship between cloud spectral relative dispersion (e) and cloud droplet number concentration (N c ) is studied. The results indicate that the value of e varies between 0.2 to 0.8 when the cloud droplet number concentration is low (about 50 cm À3 ), and converges toward a narrow range of 0.4 to 0.5 when the cloud number concentration is higher. Because the distribution of the cloud droplet size is an important parameter in estimating the first indirect radiative effect of aerosols on the climate system, the uncertainty in the corresponding radiative forcing can be reduced by 10-40% (depending on cloud droplet number density) under high aerosol loading.. This finding is important for improving climate change projections, especially for the regions where aerosol loading is high and continues to increase.Citation: Zhao, C., and et al. (2006), Aircraft measurements of cloud droplet spectral dispersion and implications for indirect aerosol radiative forcing, Geophys.

BackgroundThe problem of anti-malarial drug resistance is a long-term challenge faced by malaria control in Yunnan Province. Recently, the detection rates of chloroquine-resistant molecular markers (Plasmodium falciparum chloroquine resistant transporter, Pfcrt) and artemisinin-resistant molecular markers (P. falciparum kelch13 gene, ork13) were 85% and 35%, respectively. To understand the association of k13 gene mutation with artemisinin resistance in falciparum malaria cases, the difference in k13 gene differentiation between two populations and artemisinin resistance phenotype on falciparum malaria cases in Myanmar were analysed in this study.MethodsThis research involved all of falciparum malaria cases diagnosed continuously in Yunnan Province from 2013 to 2015 and some of falciparum malaria cases found in Lazar, Myanmar. Blood samples were taken from the former group for molecular epidemiological analysis of k13 gene mutations, and artemisinin resistance phenotypes of P. falciparum were observed in the latter group using the in vivo testing method recommended by the World Health Organization. Nested PCR was used to amplify the propeller domain of the k13 gene in P. falciparum, followed by sequencing.ResultsA total of 202 blood samples were collected from Yunnan Province and 382 blood samples were collected from falciparum malaria cases in Myanmar. 49 of 382 Myanmar cases were in vivo tested for artesunate resistance phenotype through full treatment course observation. At the same time, all the blood samples were screened for k13 gene mutation of P. falciparum. The genetic diversity of k13 was higher in the Plasmodium isolates from Yunnan Province than those from Myanmar cases. The genetic differentiation index of the two populations was 0.0410, where the intra- and inter-group variations were 95.9% and 4.1%, respectively. The odds ratio of artemisinin resistance phenotype and mutation at the locus 446 in k13 gene in Myanmar cases was 1.640, while the value was 1.840 based on the estimations of the mutations in the 12 loci.ConclusionAlthough the Plasmodium isolates from Yunnan Province and those from Myanmar were collected from different sites, they still belong to the same geographical population. It is, therefore, reasonable to contrast the artemisinin resistance status of the Plasmodium population from Myanmar with the Plasmodium population from Yunnan Province. As a result, based on the molecular epidemiological investigation on k13 mutations of Plasmodium isolates in Yunnan Province and the determination of the artemisinin resistance on falciparum malaria cases in Myanmar, the positively genetic correlated was found between the k13 locus mutations with artemisinin resistance phenotype. This provides a basis for further monitoring the artemisinin resistance by detection some molecular markers in k13 gene of Plasmodium in Yunnan Province.