Exploring structure-activity relationships around the phosphomannose isomerase inhibitor AF14049 via combinatorial synthesis

Phosphomannose Isomerase (PMI) has been shown by genetic methods to be an essential enzyme in fungal cell wall biosynthesis. The PMI inhibitor AF14049 was discovered as an unanticipated side product from high-throughput library screening against the enzyme from C, albicans. Solid-phase synthetic methods were developed and a series of libraries and discrete analogs synthesized to explore SAR around AF14049.     

LASIK for hyperopia and hyperopic astigmatism--results of a pilot study

1. The cardiac anticholinergic effects of procainamide (1 mg kg(-1) min(-1)) and its N-acetylated metabolite (NAPA) at equimolar dose (1.16 mg kg(-1) min(-1)) were studied using in vivo experimental pharmacological and in vitro radioligand binding studies. 2. Procainamide and NAPA progressively reduced vagal stimulation-induced bradycardia in chloralose-anaesthetized dogs. As indicated by the ED50, the vagolytic activity of NAPA is 1.5-2.0 times weaker than that of procainamide. Both drugs increased heart rate, with lowering of mean blood pressure during the second part of procainamide infusion, but not during NAPA infusion. 3. Binding studies on rat heart membranes yielded Ki values that were 1.5 times higher for NAPA than for procainamide. 4. These results show that NAPA exerts a weaker cardiac vagolytic action than procainamide, which is probably linked to a lower ability to bind to cardiac muscarinic receptors.     

Directed selection of MIP-1 alpha neutralizing CCR5 antibodies from a phage display human antibody library

The seven trans-membrane chemokine receptor CCR-5 is a coreceptor for macrophage tropic HIV-1 strains. CCR-5 responds to a number of chemokines, including macrophage inflammatory protein (MIP)-1 alpha. We describe the use of MIP-1 alpha in a biotin tyramine-mediated proximity selection to guide the selection of CCR-5-specific phage antibodies from a large phage display human library. Proximity based selections resulted in a population of antibodies recognizing CCR-5 on primary CD4+ lymphocytes, none of which blocked MIP-1 alpha binding to cells. The selected population of phage antibodies were subsequently used as guide molecules for a second phase of selection that was carried out in the absence of MIP-1 alpha. This generated a panel of CCR-5-binding antibodies, of which around 20% inhibited MIP-1 alpha binding to CD4+. The single chain Fvs (scFv) generated by this step-back selection procedure also inhibited MIP-1 alpha-mediated calcium signaling.     

A new metal-binding site in photosynthetic bacterial reaction centers that modulates QA to QB electron transfer

Isolated reaction centers (RCs) from Rhodobacter sphaeroides were found to bind Zn(II) stoichiometrically and reversibly in addition to the 1 equiv of non-heme Fe(II). Metal and EPR analyses confirm that Zn(II) is ligated to a binding site that is distinct from the Fe site. When Zn(II) is bound to this site, electron transfer between the quinones QA and QB (QA-QB --> QAQB-) is slowed and the room-temperature kinetics become distributed across the microsecond to millisecond time domain. This effect of metal binding on the kinetics is similar to the more global effect of cooling RCs to 2 degreesC in the absence of Zn(II). This suggests that Zn(II) binding alters localized protein motions that are necessary for rapid QA-QB --> QAQB- electron transfer. Inspection of the RC crystal structure suggests a cluster of histidine ligands located beneath the QB binding pocket as a potential binding site.     

Women's evaluation of the labor and delivery experience

The purpose of this study was to identify how women described and evaluated their labor and delivery experience and what factors were related to their responses. Sixty Lamaze-prepared, married multigravidae, aged 21 to 37 years, participated in this qualitative field study. Detailed, open-ended tape-recorded interviews were conducted on the postpartum unit of a community hospital or in the women's homes early during the postpartum period. Women evaluated their labor and delivery experience according to how well they perceived they had managed their own childbirth performance. Women who managed well viewed childbirth as positive, whereas women who had difficulty or managed poorly viewed it as both positive and negative. Women who managed well thought their own performance and the nature of labor and delivery (physical aspects) went well; women who had difficulty thought labor and delivery and the performance of others went well, but women who managed poorly had problems identifying anything that went well. There was overall agreement that the baby was the best part of the experience and that pain and pushing were the worst parts. Since women's evaluation of their labor and delivery experience may be related to the quality of their subsequent mothering, it is important to enhance their perceptions of their own performance, and thus their evaluation of the childbirth experience.     

The burnout of nursing staff working with challenging behaviour clients in hospital-based bungalows and a community unit

The increasing presence of genotoxic chemicals in the aquatic environment has led to the development of both in vivo and in vitro assays for target species. The fish population represents an important level of aquatic ecosystems that can be threatened by increased environmental pollution. The authors have studied the DNA pattern of the RTG-2 fish cell line, a fibroblast-like cell line, derived from rainbow trout (Oncorhynchus mikyss), to use this cell line as an in vitro system to study genotoxicity by means of random amplified polymorphic DNA primers (RAPDs). A constant pattern in the DNA band is essential when an organism or cell line is used to detect DNA alterations produced by genotoxic environmental chemicals. DNA fingerprints with RAPDs were obtained for RTG-2 by testing 26 single and 70 pairwise combinations of primers. Different methods of DNA extraction (chelating resin, salting out, and phenolization), the influence of spectrometric measures at 320 nm in the 260/280 quotient to quantify DNA extracts, genomic DNA and primer concentrations, annealing temperatures, and cell line passage were studied in the cell line characterization. RAPD products were identified by agarose gel electrophoresis. The good results obtained should allow the use of this system as a possible tool for detection of the genotoxicity of aquatic pollutants.     

Needed research on the interactions of certain parasitic diseases and nutrition in humans

For the purpose of assigning priorities for research, each of the following parasitic disease is examined in regard to its affect on the nutritional status of the host: schistosomiasis, malaria, amebiasis, giardiasis, ascariasis, and hookworm. The epidemiology, diagnosis, immune response to, and available therapies for these diseases are discussed. It is suggested that highest priority be given to three diseases: hookworm, ascariasis, and schistosomiasis, because they can be treated successfully, diagnosed easily, and have a high prevalence.