Pharmacological activities of trimetoquinol and 1-benzyl halogen-substituted analogues on rat beta-adrenoceptor subtypes

The beta-adrenoceptor activity profile of trimetoquinol and its 1-benzyl halogen-substituted analogues was studied in rat tissues containing primarily beta 1 (atria)-, beta 2 (trachea)- and atypical beta/beta 3 (distal colon and brown adipose tissue)-adrenoceptors. Functional biological activity resided in the (-)-isomer of trimetoquinol which was 112-, 275-, 372- and 513-fold more potent than (+)-trimetoquinol in trachea, right atria, distal colon and brown adipose tissue, respectively. (+/-)-Trimetoquinol was equally or slightly less active than (-)-trimetoquinol. The 1-benzyl halogen-substituted analogues of trimetoquinol exhibited differential activation of beta-adrenoceptor subtypes. In functional assays, 3'-iodotrimetoquinol was a potent activator of all beta-adrenoceptor subtypes. 3',5'-Diiodotrimetoquinol was 10-fold more potent as an agonist in tissues containing atypical beta/beta 3-adrenoceptors than those tissues containing beta 1- and beta 2-adrenoceptor sites. Furthermore, this drug was a partial agonist as compared to (+/-)-trimetoquinol and 3'-iodotrimetoquinol on beta 1-adrenoceptors. Pharmacological properties of the compounds on rat beta 3-adrenoceptors expressed in Chinese hamster ovary (CHO) cells were consistent with results observed in functional assays. 3',5'-Diiodotrimetoquinol possessed the greatest potency for activation of adenylyl cyclase. Rank order of affinity for rat beta 3-adrenoceptor was 3'-iodotrimetoquinol = 3',5'-diiodotrimetoquinol > (+/-)-trimetoquinol > (-)-isoprenaline. These results suggest that 3',5'-diiodotrimetoquinol is a promising drug for further chemical modification in the development of selective beta 3-adrenoceptor ligands.     

Multiple isotope effects as a probe of proton and hydride transfer in the 6-phosphogluconate dehydrogenase reaction

Primary solvent deuterium, primary substrate deuterium, multiple solvent deuterium/substrate deuterium, and multiple solvent deuterium/13C isotope effects on V/K6PG have been measured for the Candida utilis and sheep liver 6-phosphogluconate dehydrogenases (6PGDH). Proton inventory data suggest the presence of a significant medium effect in a step preceding hydride transfer and the presence of a kinetic solvent deuterium isotope effect on hydride transfer. Multiple isotope effect data confirm the presence of multiple solvent deuterium sensitive steps, likely including a conformational change preceding hydride transfer, hydride transfer, and decarboxylation.     

Cloning and recombinant expression of a barred sand bass (Paralabrax nebulifer) cDNA. The encoded protein displays structural homology and immunological crossreactivity to human complement/cofactor related plasma proteins

A new cofactor related cDNA in the bony fish Paralablax nebulifer, (barred sand bass) was isolated from a sand bass liver cDNA library. The clone (c71) is 1040 bp in size and the predicted translation product of 204 amino acids contains a hydrophobic signal peptide, which is followed by a region of three short consensus repeats (SCRs). The three SCRs display high homology to SCRs of the 110 kDa chain of the sand bass plasma cofactor protein, and to a lesser degree to human complement factor H related protein 3 (FHR-3) and to human factor H. Recombinant expression of the c71 cDNA in the baculovirus system shows a product of an apparent molecular mass of 27 kDa, which is secreted and glycosylated. It also contains a His-tag for purification purposes. Removal of the His-tag yields a 24 kDa protein, and deglycosylation further reduces the molecular mass to 21 kDa. This size is in agreement with the calculated molecular mass based on amino acid composition. The sand bass SBCFR-1 protein is immunologically related to the human complement proteins, factor H and factor H-related protein 3. The recombinantly expressed protein reacted with antisera against the human FHR-3 protein and SCRs 19-20 of human factor H. The presence of SCR-containing proteins in sand bass plasma and their structural and immunological homology to human FHR-3 and factor H suggests for a common function between these evolutionary related proteins.     

Creep deformation behavior of Sn-3.5Ag solder at small length scales

To adequately characterize the behavior of solder spheres in electronic packaging, their mechanical behavior needs to be studied at small-length scales. The creep behavior of single Sn-3.5Ag solder spheres on a copper substrate was studied between 25°C and 130°C using a microforce testing system. In the low-stress regime, the creep stress exponent changed from 6 at lower temperatures to 4 at higher temperatures, indicating creep by dislocation climb. The activation energy for creep was also found to be temperature dependent, and correlated with values for dislocation core diffusion and lattice diffusion in pure tin. A change in the stress exponent with increasing stress was also observed and explained in terms of a threshold stress for dislocation motion, due to the presence of obstacles in the form of Ag₃Sn particles. For more information, contact N. Chawla, Arizona State University, Department of Chemical and Materials Engineering, Ira A. Fulton School of Engineering, Tempe, AZ 85287-6006; e-mail nchawla@asu.edu.     

Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas

Germ-line mutations in the genes encoding succinate dehydrogenase complex subunits B (SDHB) and D (SDHD) have been reported in familial paragangliomas and apparently sporadic phaeochromocytomas (ASP), but the genotype-phenotype relationships of these mutations are unknown. Eighty-four patients (all but 2 followed up for 8.8 +/- 5.7 years) with ASP (57 with adrenal tumors, 27 with extra-adrenal, multiple, malignant, or recurrent tumors) were screened for the major susceptibility genes for phaeochromocytoma (RET, VHL, SDHD, and SDHB). Thirty-three tumors were available for molecular analysis, enzyme assays, and immunohistochemistry. No (0%) RET and 2 (2.4%) VHL mutations were detected. Only two coding single nucleotide polymorphisms in the SDHD gene (G12S and H50R) were found in 6 patients (7%). Conversely, six deleterious mutations in the SDHB gene were identified in 8 patients (9.5%). Ectopic site and recurrence or malignancy were strongly associated with SDHB mutations (7 of 8, 87%, versus 20 of 76, 26%; P = 0.001). Somatic DNA analysis indicated a loss of heterozygosity at chromosome 1p36 (SDHB locus) in 16 of 33 cases (48%). A loss of heterozygosity at the SDHB locus was found in all tumors with SDHB mutation, and assays of respiratory chain enzymes showed a complete loss of complex II catalytic activity. The vascular architecture of tumors with SDHB mutations displayed features typical of malignancy. These data strongly suggest that SDHB gene is a tumor suppressor gene and that the identification of germ-line mutations in SDHB gene in patients with ASPs should be considered as a high-risk factor for malignancy or recurrence.     

Effects of cooling rate on creep behavior of a Sn-3.5Ag alloy

The effect of cooling rate on microstructure and creep behavior of bulk, eutectic Sn-3.5Ag solders was studied. The cooling rate is an important processing variable that significantly affects the microstructure of the solder and therefore determines its mechanical behavior. Controlled cooling rates were obtained by cooling specimens in different media: water, air, and furnace, which resulted in cooling rates of 24°C/s, 0.5°C/s, and 0.08°C/s, respectively. The cooling rate decreased the secondary dendrite arm size and the spacing of the Sn-rich phase, as well as the morphology of Ag₃Sn. The Sn-dendrite arm size and spacing were smaller at fast cooling rates, while slower cooling rates yielded a nearly eutectic microstructure. The morphology of Ag₃Sn also changed from relatively spherical, at faster cooling rates, to needlelike for slower cooling. The effect of cooling rate on creep behavior was studied at 25°C, 60°C, 95°C, and 120°C. Faster cooling rates were found to increase the creep strength of the solder due to the refinement of the solder microstructure. Stress exponents, n, indicated that dislocation climb was the controlling mechanism. Activation energies, for all cooling rates, indicated that the dominant diffusional mechanism corresponded to dislocation pipe diffusion of Sn. Grain boundary sliding (GBS) measurements were conducted, using both scanning electron microscopy (SEM) and atomic force microscopy (AFM). It was observed that GBS had a very small contribution to the total creep strain.     

Circadian rhythms in human body composition

The study investigates how the human body composition (BC) changes as a function of the day-night cycle. The BC was investigated using bioelectrical impedance analysis (BIA) of 10 clinically healthy subjects (CHS), monitored in supine position (readings at 2-h intervals), avoiding mealtimes, dietary abuses, and bladder and intestinal retention. Time series data were analyzed for their temporal characteristics and circadian rhythm (CR). All the variables of BC (lean body mass, fat body mass, body cell mass, total body water, intracellular and extracellular body water, sodium and potassium exchangeable pool) showed a within-day variability with nighttime crests. Such an oscillatory synchronism corroborates the hypothesis that the rest time plays a fundamental role, via its anabolic effects, in conferring the nocturnal phase to the CR of the human BC.     

Effects of cooling rate on the microstructure and tensile behavior of a Sn-3.5wt.%Ag solder

The tensile behavior and microstructure of bulk, Sn-3.5Ag solders as a function of cooling rate were studied. Cooling rate is an important processing parameter that affects the microstructure of the solder and, therefore, significantly influences mechanical behavior. Controlled cooling rates were obtained by cooling specimens in different media: water, air, and furnace. Cooling rate significantly affected secondary dendrite-arm size and spacing of the Sn-rich phase, as well as the aspect ratio of Ag₃Sn. The Sn-rich dendrite-arm size and spacing were smaller for water-cooled specimens than for air-cooled specimens. Furnace cooling yielded a nearly eutectic microstructure because the cooling rate approached equilibrium cooling. The morphology of Ag₃Sn also changed from spherical, at a fast cooling rate, to a needlelike morphology for slower cooling. The changes in the microstructure induced by the cooling rate significantly affected the mechanical behavior of the solder. Yield strength was found to increase with increasing cooling rate, although ultimate tensile strength and strain-to-failure seemed unaffected by cooling rate. Cooling rate did not seem to affect Young’s modulus, although a clear coorelation between modulus and porosity was obtained. The mechanical behavior was correlated with the observed microstructure, and fractographic analysis was employed to elucidate the underlying damage mechanisms.