Identification of potent inhibitors of Plasmodium falciparum plasmepsin II from an encoded statine combinatorial library

An encoded 13,020-member combinatorial library was synthesized containing a statine core. Evaluation of this library with plasmepsin II, an aspartyl protease required for hemoglobin metabolism in the malaria parasite, led to the identification of potent and selective inhibitors as well as novel structure-activity relationships.     

Plasmalemmal pH-gradients in drug-sensitive and drug-resistant MCF-7 human breast carcinoma xenografts measured by 31P magnetic resonance spectroscopy

31p Magnetic resonance spectroscopy (MRS) was employed to investigate tumor pH in xenografts of drug-sensitive and drug-resistant MCF-7 human breast carcinoma cells. Measured extracellular pH values were found to be lower than the intracellular pH in all three tumor types investigated. The magnitude of this acid-outside plasmalemmal pH gradient increased with increasing tumor size in tumors of two drug-resistant variants of MCF-7 cells, but not in tumors of the parent (drug-sensitive) cells. The partitioning of weak-base or weak-acid drug molecules across the plasma membrane of a tumor cell is dependent upon the acid-dissociation constant (pKa) of the drug as well as the plasmalemmal pH gradient. A large acid-outside pH gradient, such as those seen in MCF-7 xenografts, can exert a protective effect on the cell from weak-base drugs such as anthracyclines and Vinca alkaloids, which have pKa values of 7.5 to 9.5. The possibility of enhancing the therapeutic efficacy of weak-base drugs by dietary or metabolic manipulation of the extracellular pH, in order to reduce or reverse the plasmalemmal pH gradient, deserves investigation.     

断层侧向封闭性的粘土涂抹势研究方法及应用

在深入分析粘土涂抹成因及其发育影响因素的基础上，根据粘土涂抹势与断层侧向封闭性之间的对应关系，建立了一套利用粘涂抹势研究断层侧向封闭性的方法，并将春应用于松辽盆地三站气田扶余和杨大城子油层的侧向封闭性研究中，其研究结果较客观地反映了该气田内气水分布规律，表明该方法对于断层侧向封闭性的研究是可行的。     

A conjugate of ristomycin A ristosaminylaglycon-polymyxin B: the spectrum of its antimicrobial action and its membranolytic activity

Antimicrobial activity of a conjugate based on two antibiotics, i.e. ristomycin A and polymyxin B was studied. The conjugate was shown to have a broad antimicrobial spectrum. In concentrations of 5 to 30 micrograms/ml it inhibited the growth of gram-positive and gram-negative bacteria and in concentrations of 5 to 40 micrograms/ml it inhibited the growth of the pathogenic clinical strains. An insignificant membranolytic action of the conjugate with respect to membranes of the susceptible bacteria and no hemolytic action on human red blood cells were detected.     

Two antipeptide monoclonal antibodies that recognize adhesive sequences in fibrinogen: identification of antigenic determinants and unrelated sequences using synthetic combinatorial libraries

Fulminant hepatic failure is infrequently seen as a consequence of acute congestive heart failure. Recognition of this entity is important as treatment directed towards heart failure should help resolve the liver failure. A case of fulminant hepatic failure due to previously unrecognized cardiomyopathy is presented. A liver transplantation was being considered for fulminant hepatic failure until hemodynamic monitoring studies demonstrated that, in fact, the patient had severe cardiomyopathy. Treatment directed at his cardiomyopathy resolved the liver failure. Therefore, prompt recognition of such a phenomenon would enable early institution of appropriate therapeutic measures with the hope of clinical benefit to the patient.     

Effect of cAMP-induced transcription on the repair of the phosphoenolpyruvate carboxykinase gene by hepatocytes isolated from young and old rats

Animal experiments suggest that the fetal brain is sensitive to nicotine. Although much attention has been given to the relation between cigarette smoking during pregnancy and neurodevelopment in children, this remains controversial. Our study describes the relationship between maternal cigarette smoking during pregnancy and babbling abilities of the 8-month-old infant. In a longitudinal cohort, information was collected at the 16th week of gestation, at delivery and when the infant was about 8 months old. At this age babbling abilities of the infant were evaluated by a health visitor during a home visit. Singleton infants without any disability born at Aarhus University Hospital, Denmark, 1991-92 and still living in the Community of Aarhus at the age of 8 months were eligible (n = 2302). Complete follow-up was obtained for 1871 children (81.3%). A dose-response-like relationship between number of cigarettes smoked per day during pregnancy and babbling abilities was found after controlling for potential confounders. Smoking 10 or more cigarettes per day during pregnancy almost doubled the risk (odds ratio [OR] = 2.0, 95% confidence interval [CI] 1.1-3.6) of the infant being a non-babbler at the examination at 8 months. Among children who were breast fed for less than 4 months this risk was even higher (OR = 2.7, CI 1.3-5.8).     

Projections of submucous neurons to the myenteric plexus in the guinea pig small intestine

Coronary venous hypertension induced by partial coronary sinus obstruction (CSO) in the dog, prevents or delays the predictable ventricular fibrillation (VF) of the early phase of acute ischemia. Also, CSO acting presumably through enhanced myocardial hydration, normalizes the inhomogenous extracellular potassium ([K+]o) accumulation, a major factor in producing the electrophysiological disparities, characteristic of arrhythmogenic substrate. To further clarify the mechanism of early ischemic VF prevention in dogs, radioactive microspheres were used to evaluate regional perfusion changes, resulting from CSO sufficient to raise the coronary sinus pressure to 40 mmHg, before and during ischemia induced by double coronary artery occlusion (CAO) (n=5). Also, global or regional unipolar electrogram mapping was used to assess changes of epicardial ventricular activation times (AT) and sequence and activation recovery intervals (ARI) during CSO, CAO and combined CSO and CAO, induced in random order (n=8). CSO did not affect regional perfusion nor improved collateral blood flow during ischemia. With CSO, AT shortened modestly over time (0.41+/-1.1 ms/min, r=0.85, P<0. 05) and ARI transiently decreased by up to 5.5%. With CAO, AT became variably delayed and isochrone map distortions were indicative of localized conduction delays or blocks, consistent with elevated [K+]o. In contrast, when CAO was preceded by CSO, AT delays were homogenous and normal activation sequence was preserved. Also, whereas with CAO, ARI shortened unequally over the ischemic region by as much as 43% at individual sites (average of 38.3+/-6.8 ms, P<0. 001), with combined CSO and CAO, ARI shortening was less pronounced and more homogenous (26.1+/-5.6 ms, P<0.05), not exceeding 29% at any site. Thus, in accordance with previous findings of enhanced [K+]o homogeneity, coronary venous hypertension reduces the disparities of activation and refractoriness of ischemia attributable, at least in part, to disparate [K+]o accumulation. Since no collateral blood flow improvement could be identified, the salutary electrophysiological effects of CSO may reflect a more homogenous extracellular environment, due to preservation of normal microvascular pressure (Pmv) and sustained filtration and lymph flow.     

Cloning and characterization of a novel upstream untranslated exon of the mouse Fgf-1 gene

Several recent studies have reported that there is an imbalance of increased oxidant status and decreased antioxidant system in women with preeclampsia and that factor might contribute to the pathogenesis of the disease. The following study examined blood levels of some of the antioxidants (glutathione, glutathione-peroxidase and -SH groups) as markers of lipid peroxidation in women with preeclampsia compared with normal gestation. Blood levels of these antioxidants were found significantly decreased in women with preeclampsia, which allowed us to speculate that there were abnormally increased levels of lipid peroxides. We believe that lipid peroxides are toxic compounds that damage endothelial cells, increase peripheral vasoconstriction and increase thromboxane synthesis and decrease prostacyclin synthesis. We consider that lipid peroxides are not the cause but the effect of oxidative stress induced by ischaemic placenta and leukocytes activation, so the contribute but not induce pathogenesis in preeclampsia.