Screening mixtures for biological activity by NMR

Development of the new drugs often involves the screening of compound libraries for biological activity. Currently, the biologically active component can only be identified if either a pure compound is being tested or if the components of a mixture are spatially separated, for example, on beads. Here, we present an NMR technique based on the transferred nuclear Overhauser effect (transfer NOE) that allows identification and structural characterization of biologically active molecules from a mixture. As an example we demonstrate that from mixtures of oligosaccharides only alpha-L-Fuc-(1-->6)-beta-D-GlcNAc-OMe binds to Aleuria aurantia agglutinin. The sign of transferred NOEs is opposite to NOEs of small molecules that do not bind to the protein and, thus, an unequivocal identification of molecules with binding activity is possible. Normally, the selection of bound ligands is further facilitated in that the absolute intensity of transfer NOEs is much greater than that of NOEs of non-binding molecules. In addition, transfer NOEs provide information on the three-dimensional structure of the ligands in the bound state. Therefore, measuring transfer NOEs of mixtures of small molecules in the presence of large molecules, like proteins, should significantly enhance the options for screening mixtures of compounds for biological activity.     

Role of the hemobiologist in the detection and prevention of post-transfusional hepatitis

To prevent post-transfusional hepatitis B and C, two epidemiologic studies were performed. The first, based on the frequencies distribution of hepatitis B virus serological markers versus sex and classes of age, has permitted the assessment of the profile of the infection in a population composed of 573 north vietnamese blood donors. There is no significant difference between men and women frequencies of HBs antigen (11.5%), anti-HBs antibody (70.2%) and anti-HBc antibody alone (3.8%), but a significant difference of no-marker frequencies: 7.8% and 17.9% in men and women respectively (X2 = 9.11; p = 0.010). The percentage of no-marker decreases when the mean age of each class increases. The second, using the increase of the serum alanine aminotransferase (ALAT) activity as an indirect marker of non-A, non-B hepatitis for determining in a population of more than 25,000 parisian blood donors, the percentage of donors eliminated. They are between 0.70 and 0.76 in women and 2.26 and 2.46 in men. These investigations can be applied to prevent the hepatitis B transmission in a population of 102 south vietnamese women in age to procreate or to determine the percentage of blood donors eliminated (3.12%) in a population of 2,950 Parisians composed in majority (50.9%) of new donors. The hemobiologist will have an important role to elaborate strategies for orientation of blood gifts with hepatitis B and C virus markers.     

Dimer interface of glutathione S-transferase from Arabidopsis thaliana: influence of the G-site architecture on the dimer interface and implications for classification

The three-dimensional structure of glutathione S-transferase from Arabidopsis thaliana has been solved at 2.2 A resolution (Reinemer et al., 1996). The enzyme forms a dimer of two identical subunits. The structure shows a new G-site architecture and a novel and unique dimer interface. Each monomer of the protein forms a separate G-site. Therefore, the requirements on the dimer interface are reduced. As a consequence, the interactions between the monomers are weaker and residues at the dimer interface are more variable. Thus, the dimer interface looses its relevance for a classification of plant glutathione S-transferases and the formation of heterodimers becomes even more difficult to predict.     

Preferential exclusion of sucrose from recombinant interleukin-1 receptor antagonist: role in restricted conformational mobility and compaction of native state

Understanding the mechanism for sucrose-induced protein stabilization is important in many diverse fields, ranging from biochemistry and environmental physiology to pharmaceutical science. Timasheff and Lee [Lee, J. C. & Timasheff, S. N. (1981) J. Biol. Chem. 256, 7193-7201] have established that thermodynamic stabilization of proteins by sucrose is due to preferential exclusion of the sugar from the protein's surface, which increases protein chemical potential. The current study measures the preferential exclusion of 1 M sucrose from a protein drug, recombinant interleukin 1 receptor antagonist (rhIL-1ra). It is proposed that the degree of preferential exclusion and increase in chemical potential are directly proportional to the protein surface area and that, hence, the system will favor the protein state with the smallest surface area. This mechanism explains the observed sucrose-induced restriction of rhIL-1ra conformational fluctuations, which were studied by hydrogen-deuterium exchange and cysteine reactivity measurements. Furthermore, infrared spectroscopy of rhlL-1ra suggested that a more ordered native conformation is induced by sucrose. Electron paramagnetic resonance spectroscopy demonstrated that in the presence of sucrose, spin-labeled cysteine 116 becomes more buried in the protein's interior and that the hydrodynamic diameter of the protein is reduced. The preferential exclusion of sucrose from the protein and the resulting shift in the equilibrium between protein states toward the most compact conformation account for sucrose-induced effects on rhIL-1ra.     

Identification of novel exons 3'' to the human SNRPN gene

This paper examines the relationship between self-efficacy and social power (expert and referent) and how the application of this relationship, leads to client adherence and compliance. Referent power is defined, including methods that health care professionals may use to develop and apply referent power. Expert power is defined and addressed in the context of referent power, self-esteem and self-efficacy as a means of promoting adherence. Self-efficacy as a concept is defined and explored in the context of social power. The relationships between self-efficacy and social power (expert and referent) are shown as important determinants of adherence and compliance. The theory of the application of referent and expert power in relationship with self-efficacy has been compared with an effective programme, yielding high compliance, at Western Psychiatric Institute and Clinic, showing the theory's relevance and applicability in determining compliance. Explored are the reasons for non-compliance in the elderly population and how the theory model can remedy these detriments for compliance. The empowerment of elderly patients through the application of this theory to medication compliance is examined. The determination of adherence and compliance is shown by the application of the relationship between self-efficacy and both expert and referent power.     

One or two incisions for nephroureterectomy in transitional cell renal pelvis tumours

A retrospective study comprising 18 patients with transitional cell renal pelvis tumours (TCPT) was carried out to evaluate the results after two different surgical procedures for nephroureterectomy. The kidney was removed by a flank incision and the lower part of the ureter by either an incision in the lower part of the abdomen or intussusception of the ureter followed by transurethral resection of the ureteral orifice. Eight patients were subjected to nephroureterectomy by means of two incisions and another eight patients underwent a simple nephrectomy followed by ureteral intus-susception and transurethral resection. Two patients received other treatments. After nephroureterectomy with a separate incision for ureterectomy, the average hospital stay was 12 days, compared with 7.5 days in patients operated upon with only one abdominal incision. Recurrence of tumour or survival was not significantly different in the two groups.     

A biased percolation model for the analysis of electronic-device degradation

The biased percolation model is proposed for investigating device degradation and failure associated with the generation of defects due to local Joule heating. The degradation processes of a thin conducting or semiconducting film is monitored by a set of relevant indicators, such as: the evolution of damage pattern, the current distribution, the film resistance and its fluctuations, the defect concentration, the film lifetime, etc. The conductor-insulator (CI) and conductor-superconductor (CS) like degradation processes are considered. The results can be used to propose non-destructive indicators to test the reliability of samples and to interpret the corresponding experiments.     

Error in the UNITY substitution rule for subscripted operators

UNITY, introduced by Chandy and Misra [ChM88], is a programming logic intended to reason about temporal properties of distributed programs. Despite the fact that UNITY does not have the full power of, for example, linear temporal logic, it enjoys popularity due to its simplicity.There was however a serious problem with the Substitution Rule. The logic is incomplete without the rule, and with the rule it is inconsistent.     

Performance evaluation of rule grouping on a real-time expertsystem architecture

Uses a Markov process to model a real-time expert system architecture characterized by message passing and event-driven scheduling. The model is applied to the performance evaluation of rule grouping for real-time expert systems running on this architecture. An optimizing algorithm based on Kernighan-Lin heuristic graph partitioning for the real-time architecture is developed and a demonstration system based on the model and algorithm has been developed and tested on a portion of the advanced GPS receiver (AGR) and manned manoeuvring unit (MMU) knowledge bases