Dis3, implicated in mitotic control, binds directly to Ran and enhances the GEF activity of RCC1

Using the two-hybrid method, we isolated a Saccharomyces cerevisiae cDNA encoding a protein homologous to Schizosaccharomyces pombe protein Dis3sp, using as bait, human GTPase Ran. The DIS3 gene is essential for viability and complements S.pombe mutant dis3-54 which is defective in mitosis. Although Dis3sc has no homology to RanBP1, it bound directly to Ran and the S.cerevisiae Ran homologue Cnr1, but not to the S.cerevisiae RCC1 homologue Srm1. Upon binding to Ran with a 1:1 molar ratio, Dis3sc enhanced a nucleotide-releasing activity of RCC1 on Ran. In the presence of Dis3sc, the K(m) of RCC1 on Ran decreased by half, while the kcat was unchanged. In vivo, Dis3sp was present as oligomers of M(r) 670-200 kDa as previously reported, and the 200 kDa oligomer of Dis3sp was found to include Spi1 and Pim1, the S.pombe homologues of Ran and RCC1, respectively. Although the biological function of the heterotrimeric oligomer consisting of Dis3, Spi1 and Pim1 is unknown, our results indicate that Dis3 is a component of the RCC1-Ran pathway.     

Quantification of creatinine kinetic parameters in patients with acute renal failure

BACKGROUND: Urea kinetic modeling (UKM) and creatinine (Cr) kinetic modeling (CKM) are used in the nutritional evaluation of end-stage renal disease (ESRD) patients. Both the UKM-derived normalized protein catabolic rate (nPCR) and the CKM-derived estimate of lean body mass (LBM) may also provide important information in critically ill acute renal failure (ARF) patients. Estimation of LBM may be particularly useful as previous data demonstrate that malnutrition adversely influences outcome in ARF patients. METHODS: Eleven critically ill ARF patients (age 52 +/- 21 years; mean +/- SD) treated with continuous venovenous hemofiltration (CVVH) were the study group. They were analyzed at steady state with a single-pool variable-volume model that determined the creatinine generation rate (GCr) by a methodology that we have previously described. RESULTS: The CVVH ultrafiltrate production rate was 913 +/- 49 ml/hr, yielding a blood Cr clearance of 15.2 +/- 0.9 ml/min and a steady state serum Cr of 3.4 +/- 1.7 mg/dl. Daily creatinine generation normalized to body wt (creatinine index: CI) was 6.3 +/- 0.8 and 10.6 +/- 3.0 mg/kg/day for females (N = 4) and males (N = 7), respectively (P < 0.05). Estimated mean LBM was 30.0 +/- 2.0 and 41.2 +/- 7.0 kg in females and males, respectively (P < 0.05), while the same parameter normalized to body wt was 0.50 +/- 0.05 and 0.52 +/- 0.10, respectively. These values are substantially lower than those previously reported for both normal and ESRD patients. Regression analysis demonstrated both GCr (r2 = 0.96; P < 0.001) and LBM (r2 = 0.96; P < 0.001) were significantly correlated with steady state serum Cr in a linear manner. However, no significant correlation (r2 = 0.06; P = 0.24) between nPCR and CI was observed. CONCLUSIONS: These data suggest critically ill ARF patients have severe somatic protein depletion. This malnourished state is likely due to deficits established prior to the development of ARF, such as those secondary to underlying chronic illnesses or prolonged hospitalization, and deficits related to acute hypercatabolism. Quantitative assessment of malnutrition in ARF patients with this CKM-based methodology may permit a better understanding of predisposing factors and, consequently, facilitate the development of interventions designed to prevent malnutrition in these patients.     

Morphometric analysis of heparin coated versus standard intra-aortic balloons

The adverse effects of systemic heparin administration has led to the development of heparin coated devices. Intra-aortic balloons are frequently used in clinical settings in which complications of systemic heparin, especially bleeding, are feared. The current study evaluated the thromboresistance of heparin coated intra-aortic balloons. Six bovine calves were chosen for the experiment. In each animal, three intra-aortic balloons were inserted, and set to the automatic mode: two in the vena cava for 15 min and 45 min, respectively, and one in the aorta for 6 hr. There were nine standard and nine heparin coated intra-aortic balloons. At the end of the procedures, three samples of each intra-aortic balloon were analyzed with scanning electron microscopy for computed analysis of the balloon surface covered with fibrin and cells. The scanning electron microscopy analysis showed no deposit at any time interval on the heparin coated sample surfaces, whereas 3.6% +/- 9.2% (mean +/- SD) of the standard sample surfaces were covered with deposits at 15 min (p = 0.06), 14.8% +/- 24.3% at 45 min (p = 0.01), and 4.4% +/- 12.4% at 6 hr (p = 0.06). Strikingly, none of the 27 heparin coated samples showed any microscopic deposits, whereas 11 of the 27 standard samples did (p < 0.002). Heparin coated intra-aortic balloons appear to be a promising strategy, especially for patients with absolute or relative contraindications to systemic heparinization.     

The role ofAzolla in curbing ammonia volatilization from flooded rice systems

By the year 2020, an additional 300 million tons of rice are needed annually to meet the demands of a growing population. If our natural resource base is to be preserved, intensification strategies should rely on integrated nutrient management, making full use of biological nitrogen fixation. TheAzolla-Anabaena complex is amongst the most effective systems of fixing nitrogen. In this paper we present evidence from greenhouse studies on the potential ofAzolla to curb the volatilization of NH₃ following the application of urea to a mixedAzolla-rice culture, providing a new incentive for developing ways of integratingAzolla in intensive rice cultivation systems.The results of a series of short term greenhouse experiments show that a full cover ofAzolla can significantly reduce losses of applied urea-N from 45 and 50% to 20 and 13% for the 30 and 60 kg N ha^–1 treatments, respectively. About one-quarter of the applied N was tied up in theAzolla biomass. The applied N inhibitedAzolla growth as well as the amount of N fixed. Inoculation with smaller quantities ofAzolla allowing for more vigorousAzolla multiplication was equally effective in reducing NH₃ volatilization and doubled the amount of¹⁵N tied-up byAzolla. The reduction in NH₃ volatilization is largely related to the depression byAzolla of the floodwater pH, which in its absence may reach values between 9 and 10 as a result of algal activity.Early rice growth responded positively to urea as well as the large quantities of appliedAzolla and increased the yield potential of the crop. Smaller quantities ofAzolla alone were not effective in this regard. The conservation of fertilizer N byAzolla, particularly when it fully covered the water, was reflected in a synergistic effect on rice dry matter production, amounting to 9% at the 30 kg N rate and 16% at the 60 kg N rate. In all likelihood this interaction is attributable to the higher efficiency of the applied N. The benefits ofAzolla in conserving basal urea-N even in small quantities (200-500 kg fresh material ha^–1), outweighed competition for the applied N and may be as important as its BNF. The most promising integratedAzolla/rice management systems emerging from our studies should be given further attention under field conditions.     

Curcumin Attenuates Environment-Derived Osteoarthritis by Sox9/NF-kB Signaling Axis

Inflammation has a fundamental impact on the pathophysiology of osteoarthritis (OA), a common form of degenerative arthritis. It has previously been established that curcumin, a component of turmeric (Curcuma longa), has anti-inflammatory properties. This research evaluates the potentials of curcumin on the pathophysiology of OA in vitro. To explore the anti-inflammatory efficacy of curcumin in an inflamed joint, an osteoarthritic environment (OA-EN) model consisting of fibroblasts, T-lymphocytes, 3D-chondrocytes is constructed and co-incubated with TNF-α, antisense oligonucleotides targeting NF-kB (ASO-NF-kB), or an IkB-kinase (IKK) inhibitor (BMS-345541). Our results show that OA-EN, similar to TNF-α, suppresses chondrocyte viability, which is accompanied by a significant decrease in cartilage-specific proteins (collagen II, CSPG, Sox9) and an increase in NF-kB-driven gene proteins participating in inflammation, apoptosis, and breakdown (NF-kB, MMP-9, Cox-2, Caspase-3). Conversely, similar to knockdown of NF-kB at the mRNA level or at the IKK level, curcumin suppresses NF-kB activation, NF-kB-promotes gene proteins derived from the OA-EN, and stimulates collagen II, CSPG, and Sox9 expression. Furthermore, co-immunoprecipitation assay shows that curcumin reduces OA-EN-mediated inflammation and chondrocyte apoptosis, with concomitant chondroprotective effects, due to modulation of Sox-9/NF-kB signaling axis. Finally, curcumin selectively hinders the interaction of p-NF-kB-p65 directly with DNA—this association is disrupted through DTT. These results suggest that curcumin suppresses inflammation in OA-EN via modulating NF-kB-Sox9 coupling and is essential for maintaining homeostasis in OA by balancing chondrocyte survival and inflammatory responses. This may contribute to the alternative treatment of OA with respect to the efficacy of curcumin.     

How much do incentives affect car purchase? Agent-based microsimulation of consumer choice of new cars—Part I: Model structure,simulation of bounded rationality,and model validation

This article presents an agent-based microsimulation capable of forecasting the effects of policy levers that influence individual choices of new passenger cars. The fundamental decision-making units are households distinguished by sociodemographic characteristics and car ownership. A two-stage model of individual decision processes is employed. In the first stage, individual choice sets are constructed using simple, non-compensatory rules that are based on previously owned cars. Second, decision makers evaluate alternatives in their individual choice set using a multi-attributive weighting rule. The attribute weights are based on a multinomial logit model for cross-country policy analysis in European countries. Additionally, prospect theory and the notion of mental accounting are used to model the perception of monetary values. The microsimulation forecasts actual market observations with high accuracy, both on the level of aggregate market characteristics as well as on a highly resolved level of distributions of market shares. The presented approach is useful for the assessment of policies that influence individual purchase decisions of new passenger cars; it allows accounting for a highly resolved car fleet and differentiated consumer segments. As a result, the complexity of incentive schemes can be represented and detailed structural changes can be investigated.     

Modeling the pH dependent hydrolysis of VX for aqueous releases

The fate of chemical warfare agents (CWAs) in aqueous environments is not well characterized. Limited physical and kinetic data are available in the open literature for this class of chemicals, in part due to the dangers associated with exposure to these compounds. As a result, the development of methods for determining the persistence and extent of impact of a waterborne chemical agent release remains largely unanswered. In this study a basic hydrolysis model was developed to track the fate of VX (O-ethyl S-(2-diisopropylaminoethyl) methylphosphonothiolate) from an instantaneous point source aqueous release. Hydrolysis product generation tracking was developed to determine the instantaneous pH within the local dispersive environment. Using instantaneous local pH values, the impact of pH on the persistence of VX hydrolysis rate was investigated for three different aqueous environments with varying dispersive conditions. Modeling results indicate that an accurate characterization of the pH dependence of the hydrolysis rate constant becomes more important in lower pH and lower turbulence environments. With this basic model, estimates of the time and extent of lethality of a VX release can be made.     

ScalaTrace: Scalable compression and replay of communication traces for high-performance computing

Characterizing the communication behavior of large-scale applications is a difficult and costly task due to code/system complexity and long execution times. While many tools to study this behavior have been developed, these approaches either aggregate information in a lossy way through high-level statistics or produce huge trace files that are hard to handle.