Cpt-Cgmp Is A New Ligand Of Epithelial Sodium Channels

Epithelial sodium channels (ENaC) are localized at the apical membrane of the epithelium, and are responsible for salt and fluid reabsorption. Renal ENaC takes up salt, thereby controlling salt content in serum. Loss-of-function ENaC mutations lead to low blood pressure due to salt-wasting, while gain-of-function mutations cause impaired sodium excretion and subsequent hypertension as well as hypokalemia. ENaC activity is regulated by intracellular and extracellular signals, including hormones, neurotransmitters, protein kinases, and small compounds. Cyclic nucleotides are broadly involved in stimulating protein kinase A and protein kinase G signaling pathways, and, surprisingly, also appear to have a role in regulating ENaC. Increasing evidence suggests that the cGMP analog, CPT-cGMP, activates αβγ-ENaC activity reversibly through an extracellular pathway in a dose-dependent manner. Furthermore, the parachlorophenylthio moiety and ribose 2’-hydroxy group of CPT-cGMP are essential for facilitating the opening of ENaC channels by this compound. Serving as an extracellular ligand, CPT-cGMP eliminates sodium self-inhibition, which is a novel mechanism for stimulating salt reabsorption in parallel to the traditional NO/cGMP/PKG signal pathway. In conclusion, ENaC may be a druggable target for CPT-cGMP, leading to treatments for kidney malfunctions in salt reabsorption

The Reionization History in the Lognormal Model

We study the evolution of baryonic gas before the reionization in the lognormal (LN) model of cosmic clustering. We show that the thermal history of the universe around the reionization can roughly be divided into three epochs: 1) cold dark age $z>z_r$, in which baryon gas is neutral, and opaque to Ly$\alpha$ photons; 2) hot dark age $z_r > z> z_{gp}$, in which a predominant part of baryon gas is ionized and hot, but it is still opaque to Ly$\alpha$ photons; 3) bright age $z<z_{gp}$, in which the universe is ionized highly enough to be transparent to Ly$\alpha$ photons. In the flat cold dark matter cosmological models given by WMAP and COBE, the difference of the two redshifts $z_r - z_{gp}$ is found to be as large as $\sim 10$ with $z_r\sim 17$ and $z_{gp}\sim 7$. This reionization history naturally yields a high optical depth to the CMB $\tau_e \simeq 0.12 - 0.19$ observed by the TE polarization of the WMAP, and a low redshift $z_{gp}$ of the appearance of the Ly$\alpha$ Gunn-Peterson trough $z_{gp} \simeq 6 - 8$ in QSO's absorption spectra. The reason why the universe stays long in an ionized, yet Ly$\alpha$ opaque, stage is because the first photo-ionization heats the intergalactic gas effectively and has balanced the gravitational clustering a long period of time. Therefore, the result of a high $\tau_e$ and low $z_{gp}$ is a common feature of all the models considered. Besides the cosmological parameters, the only free parameter we used in the calculation is $N_{ion}$, the mean ionization photons produced by each baryon in collapsed objects. We take it to be 40 - 80 in the calculation.Comment: AAS Latex file, 29 pages, 6 figures included, accepted for publication in Ap

Estimation of monthly pan evaporation using support vector machine in Three Gorges Reservoir Area, China

Pan evaporation plays a critical role in estimating water budget and modeling crop water requirements. However, it has been measured at a very limited number of meteorological stations. Estimation of pan evaporation from measured meteorological variables offers an important alternative and drawn increasing attention in the recent years. This paper investigated the performance of support vector machine (SVM) in the estimation of monthly pan evaporation using commonly measured meteorological variables in Three Gorges Reservoir Area in China. Evaluation suggested that SVM models showed remarkable performances and significantly outperformed the empirical model. The SVM model with polynomial as kernel function outperformed that with radial basis function. In the case of unavailable measurements of pan evaporation and meteorological variables to construct the SVM model, pan evaporation can be well-estimated by SVM model developed using data at other sites. The results indicated that the SVM method would be a promising alternative over the traditional approaches for estimating pan evaporation from measured meteorological variables

Proteolytic Regulation Of Epithelial Sodium Channels By Urokinase Plasminogen Activator: Cutting Edge And Cleavage Sites

Plasminogen activator inhibitor 1 (PAI-1) level is extremely elevated in the edematous fluid of acutely injured lungs and pleurae. Elevated PAI-1 specifically inactivates pulmonary urokinase-type (uPA) and tissue-type plasminogen activators (tPA). We hypothesized that plasminogen activation and fibrinolysis may alter epithelial sodium channel (ENaC) activity, a key player in clearing edematous fluid. Two-chain urokinase (tcuPA) has been found to strongly stimulate heterologous human αβγ ENaC activity in a dose- and time-dependent manner. This activity of tcuPA was completely ablated by PAI-1. Furthermore, a mutation (S195A) of the active site of the enzyme also prevented ENaC activation. By comparison, three truncation mutants of the amino-terminal fragment of tcuPA still activated ENaC. uPA enzymatic activity was positively correlated with ENaC current amplitude prior to reaching the maximal level. In sharp contrast to uPA, neither single-chain tPA nor derivatives, including two-chain tPA and tenecteplase, affected ENaC activity. Furthermore, γ but not α subunit of ENaC was proteolytically cleaved at (177GR↓KR180) by tcuPA. In summary, the underlying mechanisms of urokinase-mediated activation of ENaC include release of self-inhibition, proteolysis of γ ENaC, incremental increase in opening rate, and activation of closed (electrically \ silent\ ) channels. This study for the first time demonstrates multifaceted mechanisms for uPA-mediated up-regulation of ENaC, which form the cellular and molecular rationale for the beneficial effects of urokinase in mitigating mortal pulmonary edema and pleural effusions

Quality of reporting of systematic reviews published in “evidence-based” Chinese journals

BACKGROUND: The number of systematic reviews (SRs)/meta-analyses (MAs) has increased dramatically in China over the past decades. However, evaluation of quality of reporting of systematic reviews published has not been undertaken. The objective of this study is to evaluate the quality of reporting of SRs/MAs assessing efficacy and/or harms of clinical interventions published in “evidence-based” Chinese journals. METHODS: Web-based database searches were conducted for the Chinese Journal of Evidence-based Medicine, the Journal of Evidence-Based Medicine, the Chinese Journal of Evidence Based Pediatrics, and the Chinese Journal of Evidence-Based Cardiovascular Medicine. SRs/MAs assessing efficacy and/or harms of clinical interventions were included. The cut-off was December 31st 2011. The PRISMA statement was applied to assess the quality of reporting. Each item was assessed as follows: ‘Yes’ for total compliance, scored ‘1’; ‘partial’ for partial compliance, scored ‘0.5’; and ‘No’ for non-compliance, scored ‘0’. The review was considered to have major flaws if it received a total score of ≤15.0, minor flaws if it received a total score of 15.5 to 21.0, and minimal flaws if it received a total score 21.5 to 27.0. Odds ratios were used for binary variables, and the mean difference was used for continuous variables. Analyses were performed using RevMan 5.0 software. RESULTS: Overall, 487 SRs/MAs were identified and assessed. The included reviews had medium quality with minor flaws based on PRISMA total scores (range: 8.5–26.0; mean: 19.6 ± 3.3). The stratified analysis showed that SRs/MAs with more than 3 authors, from a university, hospital + university cooperation, multiple affiliations (≥2), and funding have significantly higher quality of reporting of SRs/MAs; 58% of the included reviews were considered to have minor flaws (total score of 15.6 to 21.0). Only 9.6% of reviews were considered to have major flaws. Specific areas needing improvement in reporting include the abstract, protocol and registration, and characteristics of the search. CONCLUSIONS: The reporting of SRs published in “evidence-based” Chinese journals is poor and needs to be improved in order for reviews to be useful. SR authors should use the PRISMA checklist to ensure complete and accurate accounts of their SRs

Molecular evolution of dimeric α-amylase inhibitor genes in wild emmer wheat and its ecological association

<p>Abstract</p> <p>Background</p> <p>α-Amylase inhibitors are attractive candidates for the control of seed weevils, as these insects are highly dependent on starch as an energy source. In this study, we aimed to reveal the structure and diversity of dimeric α-amylase inhibitor genes in wild emmer wheat from Israel and to elucidate the relationship between the emmer wheat genes and ecological factors using single nucleotide polymorphism (SNP) markers. Another objective of this study was to find out whether there were any correlations between SNPs in functional protein-coding genes and the environment.</p> <p>Results</p> <p>The influence of ecological factors on the genetic structure of dimeric α-amylase inhibitor genes was evaluated by specific SNP markers. A total of 244 dimeric α-amylase inhibitor genes were obtained from 13 accessions in 10 populations. Seventy-five polymorphic positions and 74 haplotypes were defined by sequence analysis. Sixteen out of the 75 SNP markers were designed to detect SNP variations in wild emmer wheat accessions from different populations in Israel. The proportion of polymorphic loci <it>P </it>(5%), the expected heterozygosity <it>He</it>, and Shannon's information index in the 16 populations were 0.887, 0.404, and 0.589, respectively. The populations of wild emmer wheat showed great diversity in gene loci both between and within populations. Based on the SNP marker data, the genetic distance of pair-wise comparisons of the 16 populations displayed a sharp genetic differentiation over long geographic distances. The values of <it>P</it>, <it>He</it>, and Shannon's information index were negatively correlated with three climatic moisture factors, whereas the same values were positively correlated by Spearman rank correlation coefficients' analysis with some of the other ecological factors.</p> <p>Conclusion</p> <p>The populations of wild emmer wheat showed a wide range of diversity in dimeric α-amylase inhibitors, both between and within populations. We suggested that SNP markers are useful for the estimation of genetic diversity of functional genes in wild emmer wheat. These results show significant correlations between SNPs in the α-amylase inhibitor genes and ecological factors affecting diversity. Ecological factors, singly or in combination, explained a significant proportion of the variations in the SNPs, and the SNPs could be classified into several categories as ecogeographical predictors. It was suggested that the SNPs in the α-amylase inhibitor genes have been subjected to natural selection, and ecological factors had an important evolutionary influence on gene differentiation at specific loci.</p