BIOCHEMICAL PROPERTIES OF GABA (B) RECEPTORS (BACLOFEN, ADENYLATE CYCLASE, CYCLIC-AMP, PHOSPHOLIPASE, PROTEIN KINASE C)

(gamma)-Aminobutyric acid (GABA), a neurotransmitter in the mammalian central nervous system, influences neuronal activity by interacting with at least two pharmacologically and functionally distinct receptors. GABA(,A) receptors are sensitive to blockade by bicuculline, are associated with benzodiazepine and barbiturate binding sites, and mediate chloride flux. The biochemical and pharmacolocal properties of GABA(,B) receptors, which are stereoselectively activated by (beta)-p-chlorophenyl GABA (baclofen), are less well understood. The aim of this study was to define these features of GABA(,B) receptors, with particular emphasis on their possible relationship to the adenylate cyclase system in brain.^ By themselves, GABA agonists have no effect on cAMP accumulation in rat brain slices. However, some GABA agonists markedly enhance the cAMP accumulation that results from exposure to norepinephrine, adenosine, VIP, and cholera toxin. Evidence that this response is mediated by the GABA(,B) system is provided by the finding that it is bicuculline-insensitive, and by the fact that only those agents that interact with GABA(,B) binding sites are active in this regard. GABA(,B) agonists are able to enhance neurotransmitter-stimulated cAMP accumulation in only certain brain regions, and the response is not influenced by phosphodiesterase inhibitors, although is totally dependent on the availability of extracellular calcium. Furthermore, data suggest that inhibition of phospholipase A(,2), a calcium-dependent enzyme, decreases the augmenting response to baclofen, although inhibitors of arachidonic acid metabolism are without effect. These findings indicate that either arachidonic acid or lysophospholipid, products of PLA(,2)-mediated degradation of phospholipids, mediates the augmentation. Moreover, phorbol esters, compounds which directly activate protein kinase C, were also found to enhance neurotransmitter-stimulated cAMP accumulation in rat brain slices. Since this enzyme is known to be stimulated by unsaturated fatty acids such as arachidonate, it is proposed that GABA(,B) agonists enhance cAMP accumulation by fostering the production of arachidonic acid which stimulates protein kinase C, leading to the phosphorylation of some component of the adenylate cyclase system. Thus, GABA, through an interaction with GABA(,B) receptors, modulates neurotransmitter receptor responsiveness in brain. The pharmocological manipulation of this response could lead to the development of therapeutic agents having a more subtle influence than current drugs on central nervous system function. ^

Recommended Nomenclature for the Sapphirine and Surinamite Groups (Sapphirine Supergroup)

Minerals isostructural with sapphirine-1A, sapphirine-2M, and surinamite are closely related chain silicates that pose nomenclature problems because of the large number of sites and potential constituents, including several (Be, B, As, Sb) that are rare or absent in other chain silicates. Our recommended nomenclature for the sapphirine group (formerly-aenigmatite group) makes extensive use of precedent, but applies the rules to all known natural compositions, with flexibility to allow for yet undiscovered compositions such as those reported in synthetic materials. These minerals are part of a polysomatic series composed of pyroxene or pyroxene-like and spinel modules, and thus we recommend that the sapphirine supergroup should encompass the polysomatic series. The first level in the classification is based on polysome, i.e. each group within the supergroup Corresponds to a single polysome. At the second level, the sapphirine group is divided into subgroups according to the occupancy of the two largest M sites, namely, sapphirine (Mg), aenigmatite (Na), and rhonite (Ca). Classification at the third level is based on the occupancy of the smallest M site with most shared edges, M7, at which the dominant cation is most often Ti (aenigmatite, rhonite, makarochkinite), Fe(3+) (wilkinsonite, dorrite, hogtuvaite) or Al (sapphirine, khmaralite); much less common is Cr (krinovite) and Sb (welshite). At the fourth level, the two most polymerized T sites are considered together, e.g. ordering of Be at these sites distinguishes hogtuvaite, makarochkinite and khmaralite. Classification at the fifth level is based on X(Mg) = Mg/(Mg + Fe(2+)) at the M sites (excluding the two largest and M7). In principle, this criterion could be expanded to include other divalent cations at these sites, e.g. Mn. To date, most minerals have been found to be either Mg-dominant (X(mg) > 0.5), or Fe(2+)-dominant (X(Mg) < 0.5), at these M sites. However, X(mg) ranges from 1.00 to 0.03 in material described as rhonite, i.e. there are two species present, one Mg-dominant, the other Fe(2+)-dominant. Three other potentially new species are a Mg-dominant analogue of wilkinsonite, rhonite in the Allende meteorite, which is distinguished front rhonite and dorrite in that Mg rather than Ti or FC(3+) is dominant at M7, and an Al-dominant analogue of sapphirine, in which Al > Si at the two most polymerized T sites vs. Al < Si in sapphirine. Further splitting of the supergroup based on occupancies other than those specified above is not recommended.

Hyalotekite, (Ba,Pb,K)(4)(Ca,Y)(2)Si-8(B,Be)(2)(Si,B)(2)O28F, a Tectosilicate Related to Scapolite: New Structure Refinement, Phase Transitions and a Short-Range Ordered 3B Superstructure

Hyalotekite, a framework silicate of composition (Ba,Pb,K)(4)(Ca,Y)(2)Si-8(B,Be)(2) (Si,B)(2)O28F, is found in relatively high-temperature(greater than or equal to 500 degrees C) Mn skarns at Langban, Sweden, and peralkaline pegmatites at Dara-i-Pioz, Tajikistan. A new paragenesis at Dara-i-Pioz is pegmatite consisting of the Ba borosilicates leucosphenite and tienshanite, as well as caesium kupletskite, aegirine, pyrochlore, microcline and quartz. Hyalotekite has been partially replaced by barylite and danburite. This hyalotekite contains 1.29-1.78 wt.% Y2O3, equivalent to 0.172-0.238 Y pfu or 8-11% Y on the Ca site; its Pb/(Pb+Ba) ratio ranges 0.36-0.44. Electron microprobe F contents of Langban and Dara-i-Pioz hyalotekite range 1.04-1.45 wt.%, consistent with full occupancy of the F site. A new refinement of the structure factor data used in the original structural determination of a Langban hyalotekite resulted in a structural formula, (Pb1.96Ba1.86K0.18)Ca-2(B1.76Be0.24)(Si1.56B0.44)Si8O28F, consistent with chemical data and all cations with positive-definite thermal parameters, although with a slight excess of positive charge (+57.14 as opposed to the ideal +57.00). An unusual feature of the hyalotekite framework is that 4 of 28 oxygens are non-bridging; by merging these 4 oxygens into two, the framework topology of scapolite is obtained. The triclinic symmetry of hyalotekite observed at room temperature is obtained from a hypothetical tetragonal parent structure via a sequence of displacive phase transitions. Some of these transitions are associated with cation ordering, either Pb-Ba ordering in the large cation sites, or B-Be and Si-B ordering on tetrahedral sites. Others are largely displacive but affect the coordination of the large cations (Pb, Ba, K, Ca). High-resolution electron microscopy suggests that the undulatory extinction characteristic of hyalotekite is due to a fine mosaic microstructure. This suggests that at least one of these transitions occurs in nature during cooling, and that it is first order with a large volume change. A diffuse superstructure observed by electron diffraction implies the existence of a further stage of short-range cation ordering which probably involves both (Pb,K)-Ba and (BeSi,BB)-BSi.

Estado actual de la Educación Física en la provincia de Castellón, a nivel de centros oficiales de B.U.P

El gran cariño que de siempre he sentido por la Educación Física, me ha llevado tras arduos y penosos esfuerzos, al estudio de la misma. El transcurrir de los años de aprendizaje en sus materias, hicieron surgir en mí, un cúmulo de interrogantes, que nunca quedaron resueltos con el conocimiento progresivo inherente a sus asignaturas. La E. Física como asignatura educativa, es factor importante en la formación pedagógica juvenil. Se basa en planteamientos teóricos como cualquier otra materia, pero su verdadero fundamento y sus incuestionables realizaciones, se dan en el campo práctico. A diferencia de las otras, en ésta, se precisa de instalaciones especiales y de material abundante. ¿Y su comprensión? Podemos decir que la forma en que ha estado estructurada la E. Física en nuestro país, la ha hecho poco comprensible para las personas ajenas o poco relacionadas con el tema. Como educador vocacional de ella, estos son problemas, que de siempre me han preocupado e intranquilizado. Buscando una posible aclaración de ellos, decidí realizar este trabajo, para dar luz en lo posible a la verdadera situación. ( Al menos en mi provincia). A medida que la idea tomaba cuerpo en mi mente, nuevas interrogantes de la misma índole, surgieron en otros compañeros. Confrontadas ideas, proyectos y encauzamientos, se llegó a crear una fórmula de trabajo común, aplicable a la situación española en general y con posteriores conclusiones particulares y concretas, en cada ámbito provincial. Con vistas a este objetivo, este trabajo, se basa en una serie de cuestionarios, dirigidos a las diversas personas implicadas en la enseñanza: directores, otros profesores, P. Educación Física, padres de alumnos y los alumnos. La meta, en definitiva, será conocer de una forma clara y palpable, el auténtico estado actual de la E. Física en la provincia de Castellón a nivel de Centros Oficiales de B.U.P.

Narrative of the voyage of H.M.S. Rattlesnake, commanded by the late Captain Owen Stanley during the years 1846-50, including discoveries and surveys in New Guinea, the Louisiade Archipelago, etc : to which is added Mr. E.B. Kennedy's expedition for the exploration of the Cape York Peninsula / by John Macgillivray.

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Inter- and intraspecies polymorphisms in the cholecystokinin-B/gastrin receptor alter drug efficacy

The brain cholecystokinin-B/gastrin receptor (CCK-BR) is a major target for drug development because of its postulated role in modulating anxiety, memory, and the perception of pain. Drug discovery efforts have resulted in the identification of small synthetic molecules that can selectively activate this receptor subtype. These drugs include the peptide-derived compound PD135,158 as well as the nonpeptide benzodiazepine-based ligand, L-740,093 (S enantiomer). We now report that the maximal level of receptor-mediated second messenger signaling that can be achieved by these compounds (drug efficacy) markedly differs among species homologs of the CCK-BR. Further analysis reveals that the observed differences in drug efficacy are in large part explained by single or double aliphatic amino acid substitutions between respective species homologs. This interspecies variability in ligand efficacy introduces the possibility of species differences in receptor-mediated function, an important consideration when selecting animal models for preclinical drug testing. The finding that even single amino acid substitutions can significantly affect drug efficacy prompted us to examine ligand-induced signaling by a known naturally occurring human CCK-BR variant (glutamic acid replaced by lysine in position 288; 288E → K). When examined using the 288E → K receptor, the efficacies of both PD135,158 and L-740,093 (S) were markedly increased compared with values obtained with the wild-type human protein. These observations suggest that functional variability resulting from human receptor polymorphisms may contribute to interindividual differences in drug effects.

Student mathematical proofs by Edward Stephen (?) Wigglesworth, 1788

Sheet with two handwritten mathematical proofs signed "Wigglesworth, 1788," likely referring Harvard student Edward Stephen Wigglesworth. The first proof, titled "Problem 1st," examines a prompt beginning, "Given the distance between the Centers of the Sun and Planet, and their quantities of matter; to find a place where a body will be attracted to neither of them." The second proof, titled "Problem 2d," begins "A & B having returned from a journey, had riden [sic] so far that if the square of the number of miles..." and asks "how many miles did each of them travel?"

Letters from Edward McCall to William Tudor,

Four letters regarding the inspection of the mine at Chanca and supplies advanced to their agent, B. Llaveria, as well as news on the movements of Simón Bolívar, José de la Mar, Antonio José de Sucre, and other Peruvian military leaders

Letters from Edward McCall to William Tudor,

Four letters regarding the contract to operate the silver mine at Chanca and other financial transactions related to the mine, the comings and goings of United States naval vessels, and the movements of Simón Bolívar.

[Copy of Edward Hopkins' will], [ca. 1713]

Handwritten copy of Edward Hopkins' 1657 will. Labeled on the verso as document "B."

Letter from Benjamin Colman to Edward Wigglesworth about John Leverett, 1728 March 4

Benjamin Colman wrote this letter to Edward Wigglesworth on March 4, 1728; it was sent from Colman, in Boston, to Wigglesworth, in Cambridge. The letter concerns their mutual friend, John Leverett, who had died several years before. It appears that Wigglesworth was charged with writing an epitaph for Leverett and had solicited input from Colman. Colman writes of his great admiration for Leverett, praising his "virtue & piety, wisdom & gravity [...] majesty & authority [...] eye & voice, goodness & courtesie."