Inverse agonism and neutral antagonism at cannabinoid CB1 receptors

There are at least two types of cannabinoid receptor, CB1 and CB2, both G protein coupled. CB1 receptors are expressed predominantly at nerve terminals and mediate inhibition of transmitter release whereas CB2 receptors are found mainly on immune cells, one of their roles being to modulate cytokine release. Endogenous cannabinoid receptor agonists also exist and these "endocannabinoids" together with their receptors constitute the "endocannabinoid system". These discoveries were followed by the development of a number of CB1- and CB2-selective antagonists that in some CB1 or CB2 receptor-containing systems also produce "inverse cannabimimetic effects", effects opposite in direction from those produced by cannabinoid receptor agonists. This review focuses on the CB1-selective antagonists, SR141716A, AM251, AM281 and LY320135, and discusses possible mechanisms by which these ligands produce their inverse effects: (1) competitive surmountable antagonism at CB1 receptors of endogenously released endocannabinoids, (2) inverse agonism resulting from negative, possibly allosteric, modulation of the constitutive activity of CB1 receptors in which CB1 receptors are shifted from a constitutively active "on" state to one or more constitutively inactive "off" states and (3) CB1 receptor-independent mechanisms, for example antagonism of endogenously released adenosine at A1 receptors. Recently developed neutral competitive CB1 receptor antagonists, which are expected to produce inverse effects through antagonism of endogenously released endocannabinoids but not by modulating CB1 receptor constitutive activity, are also discussed. So too are possible clinical consequences of the production of inverse cannabimimetic effects, there being convincing evidence that released endocannabinoids can have "autoprotective" roles.     

The performance of fungal xylan-degrading enzyme preparations in elemental chlorine-free bleaching for Eucalyptus pulp

Cellulase-free xylan-degrading enzyme preparations from Acrophialophora nainiana, Humicola grisea var. thermoidea and two Trichoderma harzianum strains were used as bleaching agents for Eucalyptus kraft pulp, prior to a chlorine dioxide and alkaline bleaching sequence. In comparison to the control sequence (performed without xylanase pretreatment), the sequence incorporating enzyme treatment was more effective. Removal of residual lignin was indicated by a reduction in kappa number. Overall, enzyme preparations from T. harzianum were marginally more effective in reducing pulp viscosity and chlorine chemical consumption and improving the brightness of the kraft pulp. However, the highest reduction in pulp viscosity was mediated by the xylanase preparation from A. nainiana. Xylanase pretreatment compares very favorably with that of chemical pulping. Journal of Industrial Microbiology & Biotechnology (2002) 28, 204–206 DOI: 10.1038/sj/jim/7000227 Received 27 April 2001/ Accepted in revised form 03 November 2001     

HUMAN B CELL DIFFERENTIATION: DEPENDENCE ON INTERACTIONS WITH MONOCYTES AND T LYMPHOCYTES VIA CD40, CD80 (B7.1), AND THE CD2-LIGANDS CD48 AND CD58 (LFA-3)

B cell differentiation depends on cellular interactions with T lymphocytes and monocytes via adhesion molecules (AM). In order to characterize AM which are required for B cell differentiation immunoglobulin production using unseparated peripheral blood mononuclear cells (PBMC) was studied. Unstimulated human PBMC were cultured for 9 days with mAb directed at CD2/CD48, /CD58, CD59, CD5/CD72, CD11a—CD18/CD54, CD28/CD80, CD86, CD40/CD40L, or rat CD2 (control). B cell differentiation was quantified measuring IgM and in some cases IgA, IgG, and IgE production. IgM levels were significantly reduced by mAb against CD40, CD48, CD58 and CD80. The reduction was not due to isotype switching to IgA, IgG or IgE. The role of CD40, CD48, CD58 and CD80 was further investigated after depletion of different cell types. Depletion of monocytes and NK cells resulted in no detectable IgM production irrespective of added mAbs. In contrast, IgM production was still present after depletion of T cells and NK cells. Only mAb against CD80 and CD48 significantly reduced IgM production, the reduction of IgM production by anti-CD40 mAb was less than in the presence of T cells. Importantly, anti-CD58 mAb had no effect on IgM production after T cell and NK cell depletion. Taken together, the AM CD40, CD48, CD58, and CD80 are involved in Ig production of unseparated PBMCs. In this model of B cell differentiation only the AM CD58 depend on the presence of T cells while CD48 and CD80 help was found to be T cell independent.     

Differences in the location of subcotyledonary buds among Epilobium angustifolium L., E. dodonaei Vill. and E. fleischeri Hochst. (Onagraceae) and effects on architecture and population structure

STÖCKLIN, J., 1992. Differences in the location of subcotyledonary buds among Epilobium angustifolium L., E. dodonaei Vill. and E. fleischeri Hochst. (Onagraceae) and effects on architecture and population structure . Morphological and architectural features in the two closely related pioneer plant species Epilobium dodonaei and E. fleischeri are examined in cultivation and in the field and compared with E. angustifolium. In E. angustifolium , the aerial shoot system is renewed every year from buds on horizontal roots and results in a horizontal spread and a clonal growth form. In E. dodonaei , bud formation is restricted to the hypocotyl and in larger plants to the transitional region between root and shoot. Consequently this species shows no vegetative mobility and develops a shrub-like habit. The alpine E. fleischeri combines the habit of E. angustifolium and E. dodonaei and may either develop successive generations of shoots from the transitional region between root and shoot and/or exploit new areas by horizontal roots and the formation of shoots from root buds. The simple difference in the location of renewal buds is accentuated by cumulative growth. The study shows that E. dodonaei and E. fleischeri , which often are considered as subspecies, are separated by fundamental differences in their architectural models. The ecological and demographic implications of these differences are discussed.     

Cold hardiness of some Alpine Collembola

Abstract.

• 1 Individual supercooling points ranged from -2 to -44°C for six species of springtails, five species from the Swiss Alps and one from lowland Britain. Individuals of Isotomurus alticola (Carl) and Isotoma viridis Bourlet without gut contents had substantially lower supercooling points than those containing food material.
• 2 Juveniles were more cold resistant than adults in both I.alticola and Isotoma hiemalis Schött, both with respect to supercooling point and to their survival at prolonged subzero temperatures.
• 3 Temperature and acclimation time affected the degree of supercooling of four of the Alpine species especially I.hiemalis.
• 4 Duration of culture period had no consistent influence on the supercooling potential of all the species.
• 5 Tests for glycerol in the body fluids of the five Alpine springtails were negative, but the presence of a sugar, probably glucose, together with a five carbon polyhydric alcohol was indicated by chromatography.

     

Genetic Analysis in Wood-Decaying Fungi I. Genetic Variation and Evidence for Allopatric Speciation in Pleurotus ostreatus using Phenoloxidase Zymograms and Morphological Criteria

Using electropherograms (zymograms) of the phenoloxidase laccase and characteristics of mycelial growth and fruit body production, a distinct morphological and biochemical differentiation of two geographically isolated (allopatric) populations of the wood-rotting basidiomycete Pleurotus ostreatus became evident. No limitation in their outbreeding ability was observed, however. A specific secretory mechanism for an extracellular laccase, genetically different in the two geographical races, could be detected. An approximately 1: 1 segregation of this laccase band in the F₁ generation indicates that specific secretion of this enzyme is controlled by one gene only, Different degrees of genetic variation as shown by differences in the respective laccase spectra were found in the two geographical races. Only one enzyme band out of nine multiple laccases was found to be specific for fruit bodies. The value of zymograms for chemotaxonomic purposes, for the understanding of microevolution and for determination of genetic variation in fungi is critically discussed.     

A NEW BASAL PTEROSAUR GENUS FROM THE UPPER TRIASSIC OF THE NORTHERN CALCAREOUS ALPS OF SWITZERLAND

Abstract:  A lower jaw with multicusped teeth and a number of unique characteristics was discovered in an extensive exposure of the Upper Triassic Kössen Formation in the Northern Calcareous Alps. The ramus of the jaw is high and dominated by a row of large, oval foramina that lies parallel to the tooth row. In addition, the anterior portion of the dentary exhibits a large number of nutritive foramina and small pits, which might indicate an association with a soft tissue structure and/or the presence of a keratinous cover of that area during life. All elements of the jaw are thin-walled and hollow, possibly pneumatic. Two teeth are preserved within the dentary. One is tricuspid and the other bears four cuSPS. The teeth are noticeably small in comparison with the overall size of the ramus, being only one-third of the height of the ramus. The teeth show a strong similarity to those of the well-known basal pterosaur genus Eudimorphodon , whose jaw morphology, however, clearly differs from the specimen described in this study. The dentition and the pneumatic bone structure make an assignment to the Pterosauria plausible. Based on the great number of distinct morphological characters the specimen is described as Caviramus schesaplanensis gen. et sp. nov.