Beneficial effects of S-adenosyl-L-methionine on blood-brain barrier breakdown and neuronal survival after transient cerebral ischemia in gerbils

In the present study, the effect of bradykinin on basal and precontracted mouse-isolated trachea was investigated. In basal conditions mouse-isolated tracheal rings do not respond to bradykinin. However, when the tracheal rings were precontracted with carbachol (10(-7) M) a relaxation with bradykinin (3 x 10(-9)-3 x 10(-7)) was found. The maximal response amounted 69.7+/-4.1% (n=15) with a pD2 value of 7.2+/-0.21. The selective bradykinin B2 receptor antagonist HOE 140 (10(-10)-10(-8) M) antagonized the bradykinin-induced relaxation, while the bradykinin B1 receptor antagonist des-Arg9-Leu8-bradykinin (10(-6) M) had no influence. The selective bradykinin B1 receptor agonist des-Arg9-bradykinin (10(-6) M) caused a small relaxation (8.4+/-2.5%, n=6), which could be antagonized completely by the selective bradykinin B1 receptor antagonist des-Arg9-Leu8-bradykinin (10(-6) M) while addition of the selective bradykinin B2 receptor antagonist HOE 140 (10(-8) M) was without effect. In the presence of indomethacin (10(-6) M) the relaxation of bradykinin was completely abolished. Pretreatment of the tracheal rings with capsaicin, or the presence of the selective NK1 receptor antagonist RP 67851 (10(-6) M) or the presence of the nitric oxide synthase inhibitor L-NAME (3 x 10(-4) M) had no effect on the bradykinin-induced relaxation. In conclusion, these results demonstrate that the mouse-isolated tracheal is a preparation in which bradykinin exerts a relaxant response via stimulation of bradykinin B2 receptors. This response is probably mediated by prostaglandins.     

Transport anomalies and magnetic properties of Sn x Eu1.2−x Mo6S8 alloys

We have measured the resistance R, magnetoresistance, and magnetization of sintered samples of the compounds Sn _x Eu_1.2–x Mo₆S₈, where x = 0, 0.12, 0.24, and 0.48. A large resistance anomaly beginning at T ~ 100 K and extending to low temperatures is found in all of the alloys except x = 0.48, which had a high superconducting transition temperature T _c ~ 11.3 K. The resistance anomaly, which appears to be correlated with the depression of T _c, is also correlated with a large negative magnetoresistance at temperatures T 12 K. For all samples except x = 0.48, that part of the magnetoresistance attributed to spin-flip scattering is proportional to the square of the magnetization M ² and is 30–40% of R (0) for some samples. Magnetization measurements are consistent with a spin-7/2 paramagnetic behavior of Eu²⁺ ions when allowance is made for a concentration of 20–30% nonmagnetic (J = 0) Eu³⁺ ions as determined from Mössbauer measurements. The experimental results are inconsistent with predictions of dilute magnetic alloy Kondo models. We speculate that the resistance anomaly and suppression of T _c for x 0.24 are associated with a semiconductor-like behavior.Work performed under the auspices of the U.S. DOE.Work supported by NSF Research Grant DMR 78-2428.     

Understanding High Critical Currents in YBa2Cu3O7 Thin Films and Coated Conductors

The main challenges for the success of high temperature superconducting wires, the YBa₂Cu₃O₇ (YBCO) coated conductors (CC), are to avoid the the weak-link problem through the production of biaxially textured films, and to increase the critical current density (J _c) through the introduction of large densities of appropriate defects. To that end, it is essential to understand the pinning mechanisms and their correlation with the microstructure of the CC. We first present a brief overview of the main methods currently used to produce YBCO CC, and we describe the architecture of the YBCO on IBAD fabricated at Los Alamos, summarizing the recent improvements of their structural and superconducting properties. Then, we analyze some aspects of the J _c dependence on temperature and magnetic field (orientation and intensity) for the best CC available, and we compare and contrast the results with those of YBCO thin films on single crystal substrates, in order to determine if the defects controlling the pinning mechanisms are the same in both cases. Our results indicate that over large field and angular ranges J _c on CC is higher than J _c in thin films on SCS.     

Crystal structures of a marginally active thymidylate synthase mutant, Arg 126-->Glu

Thymidylate synthase (TS) is a long-standing target for anticancer drugs and is of interest for its rich mechanistic features. The enzyme catalyzes the conversion of dUMP to dTMP using the co-enzyme methylenetetrahydrofolate, and is perhaps the best studied of enzymes that catalyze carbon-carbon bond formation. Arg 126 is found in all TSs but forms only 1 of 13 hydrogen bonds to dUMP during catalysis, and just one of seven to the phosphate group alone. Despite this, when Arg 126 of TS from Escherichia coli was changed to glutamate (R126E), the resulting protein had kcat reduced 2000-fold and Km reduced 600-fold. The crystal structure of R126E was determined under two conditions--in the absence of bound ligand (2.4 A resolution), and with dUMP and the antifolate CB3717 (2.2 A resolution). The first crystals, which did not contain dUMP despite its presence in the crystallization drop, displayed Glu 126 in a position to sterically and electrostatically interfere with binding of the dUMP phosphate. The second crystals contained both dUMP and CB3717 in the active site, but Glu 126 formed three hydrogen bonds to nearby residues (two through water) and was in a position that partially overlapped with the normal phosphate binding site, resulting in a approximately 1 A shift in the phosphate group. Interestingly, the protein displayed the typical ligand-induced conformational change, and the covalent bond to Cys 146 was present in one of the protein's two active sites.     

Monoamine synaptic structure and localization in the central nervous system

The monoamines dopamine, noradrenaline, adrenaline, and serotonin as well as the diamine histamine have a widespread distribution in the central nervous system within synaptic terminals and nonsynaptic varicosities. In certain regions of the central nervous system the monoamines are contained in varicosities that have no synaptic specialization associated with them, suggesting a possible neuromodulatory role for some of the monoamines. The majority of monoamine labelled structures are synaptic terminals which are characterized by the presence of small, clear vesicles (40–60 nm) and large, granular vesicles (70–120 nm) within the terminal. A third population of vesicles—small, granular vesicles—which are visible only after histochemical staining, are probably the equivalent of the small, clear vesicles present after either autoradiographic or immunohistochemical labelling. Most monoamine containing terminals contact dendrites and dendritic spines and, less frequently, neuronal somata and other axons. Both asymmetrical and symmetrical membrane specializations are associated with monoaminergic terminals; however, asymmetrical contacts are the most frequent type found. These ultrastructural results indicate that monoamine containing terminals and varicosities in general share many common morphological features, but still have diverse functions.