Abstract.A new method for parametric uncertainty analysis of nu.merical geophysical models is presented. It approximates model response surfaces, which are functions of model input parameters, using orthogonal polynomials, whose weighting functions are the probabilistic density functions (PDFs) of the input uncertain parameters. This approach has been applied to the uncertainty analysis of an analytical model of the direct radiative forcing by anthropogenic sulfate aerosols which has nine uncertain parameters. This method is shown to generate PDFs of the radiative forcing which are very similar to the exact analytical PDF. Compared with the Monte Carlo method for this problem, the new method is a factor of 25 to 60 times faster, depending on the error tolerance, and exhibits an exponential decrease of error with increasing order of the approximation.

Abstract.Hydrogen sulfide (H 2 S) takes part in a diverse range of intracellular pathways and hss physical and pathological properties in vitro and in vivo. However, the effects of H 2 S on cancer are controversial and remain unclear. The present study investigates the effects of H 2 S on liver cancer progression via activating NF-κB pathway in PLC/PRF/5 hepatoma cells.

Abstract. Hyperglycemia has been reported to activate the nuclear factor-κB (NF-κB) pathway. We have previously demonstrated that exogenous hydrogen sulfide (H 2 S) protects cardiomyocytes against high glucose (HG)-induced injury by inhibiting the activity of p38 mitogen-activated protein kinase (MAPK), which can activate the NF-κB pathway and induce interleukin (IL)-1β production. In the present study, we aimed to investigate the hypothesis that exogenous H 2 S protects cardiomyocytes against HG-induced injury and inflammation through the inhibition of the NF-κB/IL-1β pathway. H9c2 cardiac cells were treated with 35 mM glucose (HG) for 24 h to establish a model of HG-induced damage. Our results demonstrated that treatment of the cells with 400 µM sodium hydrogen sulfide (NaHS, a donor of H 2 S) or 100 µM pyrrolidine dithiocarbamate (PDTC, an inhibitor of NF-κB) for 30 min prior to exposure to HG markedly attenuated the HG-induced increase in the expression levels of the phosphorylated (p)-NF-κB p65 subunit. Notably, pre-treatment of the H9c2 cardiac cells with NaHS or PDTC significantly suppressed the HG-induced injury, including cytotoxicity, apoptosis, oxidative stress and mitochondrial insults, as evidenced by an increase in cell viability, as well as a decrease in the number of apoptotic cells, the expression of cleaved caspase-3, the generation of reactive oxygen species (ROS) and the dissipation of mitochondrial membrane potential (MMP). In addition, pre-treatment of the cells with NaHS or PDTC ameliorated the HG-induced inflammatory response, leading to a decrease in the levels of IL-1β, IL-6 and tumor necrosis factor-α (TNF-α). Importantly, co-treatment of the H9c2 cells with 20 ng/ml IL-1 receptor antagonist (IL-1Ra) and HG markedly reduced the HG-induced increase in p-NF-κB p65 expression, cytoto xicity, the number of apoptotic cells, as well as the production of TNF-α. In conclusion, the present study presents novel mechanistic evidence that exogenous H 2 S protects H9c2 cardiac cells against HG-induced inflammation and injury, including cytotoxicity, apoptosis, overproduction of ROS and the dissipation of MMP, by inhibiting the NF-κB/IL-1β pathway. We also provide new data indicating that the positive interaction between the NF-κB pathway and IL-1β is critical in HG-induced injury and inflammation in H9c2 cardiac cells.

Nannocystin A is a 21-membered cyclodepsipeptide showing remarkable anticancer properties. Described is the total synthesis of nannocystin A, which features an asymmetric vinylogous Mukaiyama aldol reaction for efficient assembly of the penultimate open-chain precursor and a pivotal intramolecular Heck cross-coupling for the final macrocyclization.

What is already known • Dexmedetomidine is a safe and efficacious sedative agent, and can offer some benefit for adult patients undergoing cardiac surgery. What this article adds • Perioperative dexmedetomidine treatment improves the outcomes in children undergoing congenital heart disease surgery, including more stable hemodynamics, shorter ventilation duration, and lesser incidence of postop-erative agitation, and rescue analgesia. Summary Background: Dexmedetomidine decreases cardiac complications in adults undergoing cardiovascular surgery. This systematic review assessed whether perioperative dexmedetomidine improves congenital heart disease (CHD) surgery outcomes in children. Methods: The PubMed, Embase, and Cochrane Library databases were searched for randomized controlled trials (RCTs) or observational studies that were published until 16 April 2015 and compared dexmedetomidine with placebo or an alternative anesthetic agent during pediatric CHD surgery. The assessed outcomes included hemodynamics, ventilation length, intensive care unit (ICU) and hospital stays, blood glucose and serum cortisol levels, post-operative analgesia requirements, and postoperative delirium. Results: Five RCTs and nine observational studies involving 2229 patients were included. In pooled analyses, dexmedetomidine was associated with shorter length of mechanical ventilation (mean difference: À93.36, 95% CI: À137.45, À49.27), lower postoperative fentanyl (mean difference: À24.11, 95% CI: À36.98, À11.24) and morphine (mean difference: À0.07, 95% CI: À0.14, 0.00) requirements, reduced stress response (i.e., lower blood glucose and serum cortisol levels), and lower risk of delirium (OR: 0.39, 95% CI: 0.21, 0.74). The hemodynamics of dexmedetomidine-treated patients appeared more stable, but there were no significant differences in the ICU or hospital stay durations. Dexmedetomidine may increase the bradycardia and hypotension risk (OR: 3.14, 95% CI: 1.47, 6.69). Conclusions: Current evidence indicates that dexmedetomidine improves outcomes in children undergoing CHD surgery. However, this finding largely relies on data from observational studies; high-quality RCTs are warranted because of the potential for subject selection bias.

Hyperglycemia, as well as diabetes mellitus, has been shown to impair ATP-sensitive K+ (KATP) channels in human vascular smooth muscle cells. Hydrogen sulfide (H2S) is also known to be an opener of KATP channels. We previously demonstrated the cardioprotective effects exerted by H2S against high-glucose (HG, 35 mM glucose)-induced injury in H9c2 cardiac cells. As such, we hypothesized that KATP channels play a role in the cardioprotective effects of H2S against HG-induced injury. In this study, to examine this hypothesis, H9c2 cardiac cells were treated with HG for 24 h to establish a model of HG-induced insults. Our findings revealed that treatment of the cells with HG markedly decreased the expression level of KATP channels. However, the decreased expression of KATP channels was reversed by the treatment of the cells with 400 µM sodium hydrogen sulfide (NaHS, a donor of H2S) for 30 min prior to exposure to HG. Additionally, the HG-induced cardiomyocyte injuries, including cytotoxicity, apoptosis, oxidative stress and mitochondrial damage, were ameliorated by treatment with NaHS or 100 µM diazoxide (a mitochondrial KATP channel opener) or 50 µM pinacidil (a non-selective KATP channel opener) for 30 min prior to exposure to HG, as indicated by an increase in cell viability, as well as a decrease in the number of apoptotic cells, the expression of cleaved caspase-3, the generation of reactive oxygen species (ROS) and the dissipation of mitochondrial membrane potential (MMP). Notably, treatment of the H9c2 cardiac cells with 100 µM 5-hydroxydecanoic acid (5-HD, a mitochondrial KATP channel blocker) or 1 mM glibenclamide (Gli, a non-selective KATP channel blocker) for 30 min prior to treatment with NaHS and exposure to HG significantly attenuated the above-mentioned cardioprotective effects exerted by NaHS. Notably, treatment of the cells with 500 µM N-acetyl‑L‑cysteine (NAC, a scavenger of ROS) for 60 min prior to exposure to HG markedly reduced the HG-induced inhibitory effect on the expression of KATP channels. Taken together, our results suggest that KATP channels play an important role in the cardioprotective effects of exogenous H2S against HG-induced injury. This study also provides novel data demonstraring that there is an antagonistic interaction between ROS and KATP channels in HG-exposed H9c2 cardiac cells.

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Background: Dysregulation of polycomb chromobox (CBX) proteins that mediate epigenetic gene silencing contributes to the progression of human cancers. Yet their roles in clear cell renal cell carcinoma (ccRCC) remain to be explored. Methods: The expression of CBX4 and its clinical significance were determined by qRT-PCR, western blot, immunohistochemistry and statistical analyses. The biological function of CBX4 in ccRCC tumor growth and metastasis and the underlying mechanism were investigated using in vitro and in vivo models. Findings: CBX4 exerts oncogenic activities in ccRCC via interaction with HDAC1 to transcriptionally suppress tumor suppressor KLF6. CBX4 expression is increased in ccRCC and correlated with poor prognosis in two independent cohorts containing 840 patients. High CBX4 expression is significantly associated with Fuhrman grade and tumor lymph node invasion. CBX4 overexpression promotes tumor growth and metastasis, whereas CBX4 knockdown results in the opposite phenotypes. Mechanistically, CBX4 downregulates KLF6 via repressing the transcriptional activity of its promoter. Further studies show that CBX4 physically binds to HDAC1 to maintain its localization on the KLF6 promoter. Ectopic expression of KLF6 or disruption of CBX4-HDAC1 interaction attenuates CBX4-mediated cell growth and migration. Furthermore, CBX4 depletion markedly enhances the histone deacetylase inhibitor (HDACi)-induced cell apoptosis and suppression of tumor growth. Interpretation: Our data suggest CBX4 as an oncogene with prognostic potential in ccRCC. The newly identified CBX4/HDAC1/KLF6 axis may represent a potential therapeutic target for the clinical intervention of ccRCC.