Plasma membrane cholesterol is a key molecule in shear stress-dependent activation of extracellular signal-regulated kinase

Shear stress, the dragging force generated by fluid flow, differentially activates extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) in bovine aortic endothelial cells (BAEC) (Jo, H., Sipos, K., Go, Y. M., Law, R., Rong, J., and McDonald, J. M. (1997) J. Biol. Chem. 272, 1395-1401). Here, we examine whether cholesterol-enriched compartments in the plasma membrane are responsible for such differential regulation. Pretreatment of BAEC with a cholesterol-binding antibiotic, filipin, did not inhibit shear-dependent activation of JNK. In contrast, filipin and other membrane-permeable cholesterol-binding agents (digitonin and nystatin), but not the lipid-binding agent xylazine, inhibited shear-dependent activation of ERK. The effect of cholesterol-binding drugs did not appear to be due to membrane permeabilization, since treatment of BAEC with a detergent, Triton X-100 which also permeabilizes membranes, did not inhibit shear-dependent activation of ERK. Furthermore, shear-dependent activation of ERK, but not JNK, was inhibited by cyclodextrin, a membrane-impermeable cholesterol-binding agent, which removes cell-surface cholesterol. Moreover, the effects of cyclodextrin were prevented by adding cholesterol during the incubation. These results indicate that cholesterol or cholesterol-sensitive compartments in the plasma membrane play a selective and essential role in activation of ERK, but not JNK, by shear stress. Although exposure to shear stress (1 h) increased the number of caveolae by 3-fold, treatment with filipin had no effect in either control or shear-exposed cells suggesting that caveolae density per se is not a crucial determinant in shear-dependent ERK activation. In summary, the current study suggests that cholesterol-sensitive microdomains in the plasma membrane, such as caveolae-like domains, play a critical role in differential activation of ERK and JNK by shear stress.     

5-Fluorouracil prodrug: role of anabolic and catabolic pathway modulation in therapy of colorectal cancer

Following p.o. administration to rats bearing advanced colorectal carcinoma, Ftorafur (FT) is converted to 5-fluorouracil (FUra) by microsomal P450 in the liver. To optimize the therapeutic selectivity of the FUra generated from FT, three approaches were utilized: (a) inhibition of FUra degradation to dihydrofluorouracil by uracil as an alternative substrate for uracil reductase in the molar ratio of 4 uracil:1 FT (UFT); (b) modulation of drug inhibition of thymidylate synthase by leucovorin (LV); and (c) by increasing the level of FUra incorporation into cellular RNA by N-(phosphonacetyl)-L-aspartate (PALA), an inhibitor of aspartate transcarbomylase. The maximum tolerated dose (MTD) of FT and UFT, administered 3 times a day for 28 days, was 150 mg/kg/day and 60 mg/kg/day, respectively. The MTDs were not significantly modified by LV (150 or 600 mg/kg/day), administered by the p.o. route with the drugs, or by PALA (100 mg/kg) administered weekly by the i.v. route. The dose-limiting toxicity of FT alone and in combination with the modulators was stomatitis. The severe alopecia observed with FT alone was reduced significantly by uracil. At the MTD, the antitumor activity of UFT was superior to those of FT and FUra alone and in combination with LV and/or PALA. The 3-month sustained complete tumor regression for UFT, FT, and FUra was 38%, 0%, and 13% (for the weekly schedule), respectively. Although uracil, LV, and PALA individually increased the antitumor activity of FT at its MTD, the combination of the three modulators produced the highest therapeutic efficacy in rats bearing advanced colorectal carcinoma, in which 100% of the treated animals achieved complete and sustained tumor regression. The therapeutic efficacy observed with FT modulation could not be achieved with FUra administered by different schedules, each at its MTD alone or in combination with either LV or PALA. In brief, modulation of FT produced greater therapeutic efficacy and selectivity than FUra. Furthermore, the combined use of modulators capable of inhibiting the degradation pathway of FUra and potentiating the effects of the anabolic metabolites action appears to offer the greatest therapeutic potential.     

Distribution of rhodium in mice submitted to treatment with the adduct of rhodium propionate and sodium isonicotinate

The distribution of rhodium in Balb/c mice following intraperitoneal (ip) administration of a solution of adduct of rhodium propionate and sodium isonicotinate has been investigated. The metal concentration was determined in blood and in the following organ tissues: brain, heart, lung, liver, spleen, kidney, testes, and uterus/ovary, and the rhodium concentration was obtained by Inductively Coupled Argon Atomic Emission Spectroscopy (ICP-AES). The metal was detected in all organ tissues examined, mainly in spleen, liver, uterus/ovary and heart. Nine days after the injection, traces of rhodium were found in the liver and kidneys and, twenty days after the injection, only in the liver.     

Shear Strength of Fiber-Reinforced Sands

Soil reinforcement using discrete randomly distributed fibers has been widely investigated over the last 30 years. Several models were suggested to estimate the improvement brought by fibers to the shear strength of soils. The objectives of this paper are to (1) supplement the data available in the literature on the behavior of fiber-reinforced sands; (2) study the effect of several parameters which are known to affect the shear strength of fiber-reinforced sands; and (3) investigate the effectiveness of current models in predicting the improvement in shear strength of fiber-reinforced sand. An extensive direct shear testing program was implemented using coarse and fine sands tested with three types of fibers. Results indicate the existence of a fiber-grain scale effect which is not catered for in current prediction models. A comparison between measured and predicted shear strengths indicates that the energy dissipation model is effective in predicting the shear strength of fiber-reinforced specimens in reference to the tests conducted in this study. On the other hand, the effectiveness of the predictions of the discrete model is affected by the parameters of the model, which may depend on the test setup and the procedure used for mixing the fibers.     

Collaborative Localization for Multi-Robot System with Fault Detection and Exclusion Based on the Kullback-Leibler Divergence

Multi-robot system attracted attention in various applications in order to replace the human operators. To achieve the intended goal, one of the main challenges of this system is to ensure the integrity of localization by adding a sensor fault diagnosis step to the localization task. In this paper, we present a framework able, in addition of localizing a group of robots, to detect and exclude the faulty sensors from the group with an optimized thresholding method. The estimator has the informational form of the Kalman Filter (KF) namely Information Filter (IF). A residual test based on the Kullback-Leibler divergence (KLD) between the predicted and the corrected distributions of the IF is developed. It is generated from two tests: the first acts on the means and the second deals with the covariance matrices. Thresholding using entropy based criterion and Receiver Operating Characteristics (ROC) curve are discussed. Finally, the validation of this framework is studied on real experimental data from a group of robots.     

H凹陷三叠系小泉沟群地震相分析

在中国西部许多陆相盆地中，发育了多种各样的砂岩储集体，这些砂体在不同的沉积环境、不同的相带中有规律地分布着。文中对西部某盆地Ｈ凹陷三叠系小泉沟群地震相和沉积相进行了较详细的研究；分析了该组的岩性特征、地震相特征和剖面沉积相特征，指出了各种沉积相中的主要砂体类型及有利的含油气相带。