The diterpene, forskolin [half-maximal effective concentration (EC50), [5][6][7][8][9][10] vation of cyclic AMP in rat cerebral cortical slices that is not blocked by a variety of neurotransmitter antagonists. Low concentrations of forskolin (1 ,uM) augment the response of cyclic AMP-generating systems in brain slices to norepinephrine, isoproterenol, histamine, adenosine, prostaglandin E2, and vasoactive intestinal peptide. Forskolin would appear to activate adenylate cyclase through a unique mechanism involving both direct activation of the enzyme and facilitation or potentiation of the modulation of enzyme activity by receptors or the guanyl nucleotide-binding subunit, or both. Cyclic nucleotides regulate many cellular events (1), but it has proven difficult to firmly establish the relationship of cyclic AMP (cAMP) levels to physiological functions in intact cells, tissues, and organisms. In part, this is due to the lack of a satisfactory general activator for adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] in intact cells. Receptor-mediated activation of the enzyme is highly specific and is further dependent on interactions of an intracellular guanyl nucleotide-binding subunit with the catalytic unit of adenylate cyclase (2). Sodium fluoride (3), guanyl nucleotides (4), and divalent cations such as manganese (5, 6) and calcium (7) activate the enzyme independent of specific cell-surface receptors, but fluoride is ineffective with intact cells, and guanyl nucleotides and divalent cations require access to intracellular sites. Cholera toxin and other enterotoxins activate adenylate cyclase both in crude membranes and in intact cells, but the process is irreversible and requires interaction with a ganglioside cell-surface site (8).The hypotensive (9) diterpene forskolin ( Fig. 1) from the roots of Coleus forskohlii (10) has been reported to activate cardiac and brain adenylate cyclase (11,12 Kehr of Schering,6,8, C22H3407; Mr, 410) was generously provided by Hoechst Pharmaceuticals, Bombay, India. Forskolin is now available from CalBiochemBehring, La Jolla, CA, and has activity equivalent to that reported in this paper for the Hoechst sample. Forskolin (15 mM) was dissolved in 95% ethanol and was stable for at least 4 mo in solution. All other reagents were of the highest quality available from standard commercial sources.Preparation of Membranes. A male Sprague-Dawley rat (150-175 g) was killed by decapitation, and the brain was removed quickly, chilled briefly in ice-cold Krebs-Ringer bicarbonate/glucose buffer, and placed on a glass plate. Cerebral cortical grey matter was dissected with a razor and homogenized in 50 mM Tris-HCl buffer, pH 7.5/0.1 mM CaCl2 (5 ml per rat cortex) in a Dounce homogenizer (10 strokes). The homogenate

A diverse array of biologically active, lipid-soluble alkaloids have been discovered in amphibian skin. Such alkaloids include the following: the steroidal samandarines from salamanders, the batrachotoxins, histrionicotoxins, gephyrotoxins, and epibatidine from neotropical poison frogs (Dendrobatidae), the pumiliotoxins, allopumiliotoxins, homopumiliotoxins, and decahydroquinolines from certain genera of anurans from four families (Dendrobatidae, Mantellidae, Bufonidae, and Myobatrachidae), a variety of izidines (pyrrolizidines, indolizidines, quinolizidines, lehmizidines), pyrrolidines, piperidines, various tricyclics (related in structures to the coccinellines), and spiropyrrolizidines from the first three of these four families, the pseudophrynamines from one genus of Australian frogs, and a variety of unclassified alkaloids as yet of undetermined structure. With the exception of the samandarines and the pseudophrynamines, all alkaloids appear to be derived from dietary sources. Although only a few of the over 800 amphibian skin alkaloids have been detected in arthropods, putative arthropod sources for the batrachotoxins and coccinelline-like tricyclics (beetles), the pumiliotoxins (ants, mites), the decahydroquinolines, izidines, pyrrolidines, and piperidines (ants), and the spiropyrrolizidines (millipedes) have been discovered. Ants are likely sources for histrionicotoxins, lehmizidines, and tricyclic gephyrotoxins. Epibatidines represent an important alkaloid class without a putative dietary source. The structures for many of these alkaloids have been rigorously established, while the structures of others represent tentative proposals, based only on mass spectral and FTIR spectral data, along with analogies to structures of well-defined alkaloids.

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Abstract-The increasing importance being placed on software measurement has led to an increased amount of research developing new software measures. Given the importance of object-oriented development techniques, one specific area where this has occurred is coupling measurement in object-oriented systems. However, despite a very interesting and rich body of work, there is little understanding of the motivation and empirical hypotheses behind many of these new measures. It is often difficult to determine how such measures relate to one another and for which application they can be used. As a consequence, it is very difficult for practitioners and researchers to obtain a clear picture of the state-of-the-art in order to select or define measures for object-oriented systems.This situation is addressed and clarified through several different activities. First, a standardized terminology and formalism for expressing measures is provided which ensures that all measures using it are expressed in a fully consistent and operational manner. Second, to provide a structured synthesis, a review of the existing frameworks and measures for coupling measurement in object-oriented systems takes place. Third, a unified framework, based on the issues discovered in the review, is provided and all existing measures are then classified according to this framework.This paper contributes to an increased understanding of the state-of-the-art: A mechanism is provided for comparing measures and their potential use, integrating existing measures which examine the same concepts in different ways, and facilitating more rigorous decision making regarding the definition of new measures and the selection of existing measures for a specific goal of measurement. In addition, our review of the state-of-the-art highlights that many measures are not defined in a fully operational form, and relatively few of them are based on explicit empirical models, as recommended by measurement theory.

The increasing importance being placed on software measurement has lead to an increased amount of research developing new software measures. Given the importance of object-oriented development techniques, one specific area where this has occurred is cohesion measurement in object-oriented systems. However, despite a very interesting body of work, there is little understanding of the motivation and empirical hypotheses behind many of these new measures. It is often difficult to determine how such measures relate to one another and for which application they can be used. As a consequence, it is very difficult for practitioners and researchers to obtain a clear picture of the state-of-the-art in order to select or define cohesion measures for object-oriented systems. This situation is addressed and clarified through several different activities. First, a standardized terminology and formalism for expressing measures is provided which ensures that all measures using it are expressed in a fully consistent and operational manner. Second, to provide a structured synthesis, a review of the existing approaches to measure cohesion in object-oriented systems takes place. Third, a unified framework, based on the issues discovered in the review, is provided and all existing measures are then classified according to this framework. Finally, a review of the empirical validation work concerning existing cohesion measures is provided.This paper contributes to an increased understanding of the state-of-the-art: a mechanism is provided for comparing measures and their potential use, integrating existing measures which examine the same concepts in different ways, and facilitating more rigorous decision making regarding the definition of new measures and the selection of existing measures for a specific goal of measurement. In addition, our review of the state-of-the-art highlights several important issues: (i) many measures are not defined in a fully operational form, (ii) relatively few of them are based on explicit empirical models as recommended by measurement theory, and (iii) an even smaller number of measures have been empirically validated; thus, the usefulness of many measures has yet to be demonstrated.

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