ICI 182,780 acts as a partial agonist and antagonist of estradiol effects in specific cells of the sheep uterus

We assessed the ability of ICI 182,780 (ICI) to block the estradiol (E2) responses of genes within the sheep uterus. Ovariectomized ewes in the ‘ICI+E2’ treatment group received a uterine infusion with 10⁻⁷ M ICI for 14 h, an injection of 50 μg E2 6 h after the infusion started, and were hysterectomized 18 h postinjection. Other groups received only ICI or E2, or neither treatment (‘Con’). Both E2 and ICI increased the wet weight of dissected endometrium: averaging 10.0±1.2 g for ICI+E2, ICI, and E2 groups compared to 6.8±0.6 g for Con. Slot blot analyses of endometrial RNA showed that estrogen receptor- (ER), progesterone receptor (PR), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), cyclophilin, actin and c-fos mRNAs responded to E2 treatment: the first five increased an average of 60% while the last decreased 38%. In situ hybridization identified more subtle ICI effects: agonistic up-regulation of GAPDH mRNA in superficial endometrial cells, and antagonistic down-regulation of ER and PR mRNAs in the inner layer of the myometrium. Thus, we conclude that the agonist versus antagonist effects of ICI relative to those of E2 are a function of the gene examined as well as the specific cell within the uterus.     

A characteristic pharmacological action of ‘Yang-invigorating’ Chinese tonifying herbs: Enhancement of myocardial ATP-generation capacity

In order to investigate the pharmacological basis of ‘Yang-invigorating’ action, the effect of oral treatment with the methanolic extract of ‘Yang-invigorating’ herbs on ATP-generation capacity was examined, using heart homogenates prepared from herb-pretreated mice. Tonifying (i.e., health-promoting) herbs of other functional categories were also included for comparison. The results indicated that ‘Yang-invigorating’ Chinese tonifying herbs could invariably enhance myocardial ATP-generation capacity, with the extent of stimulation varying among the herbs. In contrast, ‘Yin-nourishing’ herbs either did not stimulate or even decreased myocardial ATP-generation capacity. While ‘Qi-invigorating’ herbs produced variable effects on myocardial ATP-generation capacity, most of the ‘blood-enriching’ herbs did not cause any significant changes. The results obtained from studies using myocardial mitochondrial fractions isolated from herb-pretreated mice suggest that ‘Yang-invigorating’ herbs might speed up ATP generation by increasing mitochondrial electron transport. The ensemble of results has provided evidence for the first time to support the pharmacological basis of ‘Yang invigoration’ in Chinese medicine.     

The anticonvulsant effects of DADLE are primarily mediated by activation of delta opioid receptors: interactions between delta and mu receptor antagonists

Dose-response comparisons of the ability of the selective delta antagonist ICI 154,129 (12.5-50 nmol), the nonselective antagonist naloxone (29-290 nmol), and the irreversible selective mu antagonist beta-fNA (1.3-21 nmol) to alter the threshold response to DADLE or etorphine was studied in the rat flurothyl seizure test. DADLE (35 nmol, i.c.v.) and etorphine (122 nmol/kg, s.c.) both caused increases in seizure threshold which were differentially antagonized by pretreatment (i.c.v.) with the respective antagonists. For DADLE, only ICI 154,129 and naloxone produced a dose-related blockade of the increase in seizure threshold, with ICI 154,129 being more potent than naloxone. In contrast, the anticonvulsant action of etorphine was not antagonized by ICI 154,129 (50 nmol), but was blocked by a low dose of naloxone (29 nmol) or beta-fNA (21 nmol). In addition, prior occupancy of mu-sites with beta-fNA (21 nmol) significantly diminished the abilities of either ICI 154, 129 (50 nmol) or naloxone (290 nmol) to antagonize the anticonvulsant action of DADLE. The results of this study demonstrated that the effects of DADLE to increase seizure threshold in the rat were primarily mediated by activation of a delta-opioid receptor system. Furthermore, evidence has been provided for a functional interaction between delta and mu receptors in the opioid regulation of seizure threshold.     

Pharmacogenomics: out of the lab and into the community

Pharmacogenomics is the study of the inherited basis of differences in response to drugs. These interindividual differences are often more than tenfold; a ‘slow metabolizer’ or ‘low-responsive’ individual might therefore require ten times less than the recommended dose of a drug than a ‘rapid metabolizer’ or ‘high-responsive’ person, and the slow metabolizer is often more likely to experience drug toxicity than a rapid metabolizer. Our knowledge is developing rapidly to the point that the physician will soon use DNA-based tests to aid in decision-making with respect to the most appropriate drug and dosage given to each patient. If the patient's DNA is available, however, what boundaries should be placed on that DNA? If the patient's genotype becomes known to the physician (and presumably to the patient him- or herself), what ethical questions might arise and how will they be resolved? This article discusses these issues and outlines some of the possible solutions.     

Emetic and antiemetic properties of regulatory peptides

Emetic and antiemetic properties of opioid peptides, substance "P", beta-lipotropin, and ACTH1-39 have been investigated in experiments on cats. It was shown that morphine, enkephalin, beta-endorphin and DADLE caused vomiting in animals, which was blocked by naloxone. Substance "P", gamma- and des-tyr-gamma-endorphin manifested antiemetic properties similar to those of naloxone. Selective antagonists of delta-opioid receptors ICI 154, 129 blocked emetic action of delta-agonist DADLE but did not prevent vomiting caused by mu-agonist morphine. It is suggested that the vomiting mechanisms of endogenous opioid peptides involve stimulation of mu- and delta-opioid receptors in the chemoreceptor trigger zone of the vomiting centre.     

Inhibition of an opioid-evoked vagal reflex in rats by naloxone,SMS 201-995 and ICI 154,129

Intravenous injection of opioid agonists in rats evokes a vagal reflex resulting in a fall in heart rate and blood pressure. Three opioid antagonists, naloxone, SMS 201-995, and ICI 154,129 were used to assess the nature of the opioid receptors that mediate the vagal reflex. The agonists used were morphine, Tyr-Pro-NMePhe-d-Pro-NH₂ (PLO17), and d-Ala²-Leu⁵-enkephalin (DADL). At challenge doses of morphine, PLO17, and DADL at five times the ED50 for bradycardia, the naloxone ED50 for DADL was nine times greater than that for morphine and PLO17. The pA₂ value of naloxone against DADL was significantly less than that for morphine and PLO17. The antagonist properties of SMS 201-995 were similar to those of naloxone. ICI 154,129, a putative delta receptor antagonist, was not, however, selective in its antagonism of opioid bradycardia. Both SMS 201-995 and ICI 154,129, when injected alone, produced changes in heart rate and blood pressure. The cardiovascular actions of the peptide antagonists were not affected by naloxone hydrochloride at doses up to 4 mg/kg i.v.     

Rheology and fracture of mixed ι- and κ-carrageenan gels: Two-step gelation

It is shown that under certain circumstances, on cooling mixed ι- and κ-carrageenan solutions, the two forms gel separately at different temperatures, with the ι form gelling first. This ‘two-step gelation’ was only observed when both sodium and potassium ions were present, with a sodium/potassium mole ratio of between 1 and 100. For such mixed gels, a κ fraction as low as 2·5% of the total carrageenan has significant effects on their rheology, both at low deformation and fracture. In these systems, the κ form, gelling in the presence of an existing ι gel, produces measurable rheological effects at much lower concentrations than if it were alone. This behaviour can be used as a sensitive test of the ‘rheological purity’ of samples of ι-carrageenan.     

Viscoelastic properties of aqueous solutions of an exocellular polysaccharide from cyanobacteria

The viscoelastic properties of aqueous solutions of the exocellular polysaccharide of Cyanospira capsulata have been studied, over a wide range of polymer concentrations, using small deformation oscillatory, steady and transient shear methods. The viscoelastic spectra generally resemble those of an entangled network, although notable deviations can be observed in the low frequency dependence of G′ and G″. At higher polymer concentrations, the viscoelastic spectrum shows solid-like behaviour over a wide range of frequencies. The superposition of η^*(ω) and η( ) curves occurs only at low frequencies, at higher frequencies the slope of η^*(ω) is lower than that of η( ). By studying the time evolution of shear stress after the inception of a steady shear rate (stress overshoot), the recovery of non-linear properties after steady shearing flow is seen to occur after times of c. 10³ s (in the case of 1·1% w/v solutions).

The overall viscoelastic properties appear original in comparison with those of the two structurally limiting types of polysaccharide, the ‘ordered’ chain xanthan and the ‘random coil’ guar. A rationale for this ‘anomalous’ viscoelastic behaviour can be tentatively proposed in terms of flickering intermolecular cross-interactions between semi-flexible segments, which occur in addition to the usual topological constraints.     

Male sterility and restored fertility in annual mercuries, relations with sex differentiation

The paper summarizes the researches conducted on male sterility in Mercurialis annua. Totally sterile individuals are very scarce in the dioecious species showing as the other Mercuries, unisexual flowers devoid of rudiments of the opposite sex. From one sterile male mutant, a ‘sterile series’ was conducted and genetics was studied. Sterile, semisterile, restored fertile male lines were constructed as well as female lines containing the inducer gene of male sterility, both fertility restorers and the sensitive cytoplasm. Morphology and ontogeny of these isogenic lines were presented. Male sterile anthers (empty) present a splitted tapetum and an abnormal meiotic end. Restored fertile male lines were normal. The relative abundance of auxin and cytokinins was studied. A specific cytokinin pathway measured as a background in fertile lines, the cis-oxidized pathway characterised the ‘sterile series’. Restoration of normal meiosis and tapetum appeared for the highest quantities of cis-zeatin (669 ng instead of 192 ng/100 g fresh weight in totally sterile). Auxin quantities were abundant compared with the normal males. Gene expression in the ‘sterile series’ was also compared with the fertile lines. t-RNAs specific for normal females were expressed in the male ‘sterile series’. Hybridization kinetics and in vitro translations pf poly(A)⁺RNAs demonstrate specific sequences for each line. Comparisons between identical organs (normal fertile male/restored fertile male or normal female/female of the ‘sterile series’) exhibited nearly 10% differences. The results suggest that for stamen development, a cascade of regulators probably exists: sex genes acting on the induction of stamen or pistil, then genes for sterility/restoration of fertility acting in anthers. Fertility-sterility regulators control the synthesis of a specific cytokinin pathway. The new hormonal signals are linked to several specific genes expressed in the floral morphology characterizing each line of the ‘sterile series’.     

Determination of the polymorphic composition of smooth pea starch

A method for estimating the proportions of ‘A’ and ‘B’ polymorphs comprising a sample of ‘C’ type starch is proposed which uses established experimental techniques with commercially available spreadsheet and X-ray analysis software. Waxy maize, potato and smooth pea starches were used to provide X-ray diffraction patterns characteristic of the ‘A’, ‘B’ and ‘C’ starch polymorphs. Samples of amorphous starches were also prepared. The method initially involved subtraction of the amorphous phase and instrumental background from the X-ray diffraction patterns of each starch sample using the spreadsheet program, Lotus 1-2-3. The remainder of the pattern, representing the crystalline portion of the starch sample, was then analysed by profile fitting to elucidate the positions and areas of individual diffraction peaks. The ratio of the total peak area to the areas under peaks characteristic of ‘A’ and ‘B’ type starches, respectively, were used to calculate the relative proportions of these polymorphs in smooth pea starch. These proportions were found to be 56±3% ‘A’ polymorph to 44±3% ‘B’ polymorph. A ‘C’ type pattern was constructed by using Lotus 1-2-3 to combine diffraction patterns from the crystalline portions of ‘A’ and ‘B’ type starches in the proportions given above. Polymorph patterns were obtained by manipulation of the diffraction patterns from the crystalline portions of starches using Lotus 1-2-3. An ‘A’ type pattern was obtained by subtraction of a ‘B’ type pattern from that of a ‘C’ type. Similarly, a ‘B’ type pattern was obtained by subtraction of an ‘A’ type pattern from that of a ‘C’ type.     

Facial correlates of sociosexuality

Previous studies have documented variation in sexual behaviour between individuals leading to the notion of ‘restricted’ individuals (i.e., people who prefer long-term relationships) and ‘unrestricted’ individuals (i.e., people who are open to short-term relationships). This distinction is often referred to as sociosexual orientation. Observers have been previously found to distinguish sociosexuality from video footage of individuals, although the specific cues used have not been identified. Here we assessed the ability of observers to judge sexual strategy based specifically on cues in both facial composites and real faces. We also assessed how observers' perceptions of the masculinity/femininity and attractiveness of faces relate to the sociosexual orientation of the pictured individuals. Observers were generally able to identify restricted vs. unrestricted individuals from cues in both composites and real faces. Unrestricted sociosexuality was generally associated with greater attractiveness in female composites and real female faces and greater masculinity in male composites. Although male observers did not generally associate sociosexuality with male attractiveness, female observers generally preferred more restricted males' faces (i.e., those with relatively strong preferences for long-term relationships). Collectively, our results support previous findings that androgenisation in men is related to less restricted sexual behaviour and suggest that women are averse to unrestricted men.     

Sequence dependent hydration of DNA

The transitions between the different helical conformations of DNA depend on the base sequence and the ambient conditions such as humidity and counter-ion concentration. In this study energy minimization techniques have been used to locate water molecule sites around nucleotides especially those which form hydrogen bonds between two or more nucleotide atoms and thus form solvent mediated bridges. We have studied several sequences and find that those which are known not to exist in the low hydration ‘A’ form have very similar number of bridging sites in both ‘A’ and ‘B’ conformations. Those sequences which are found in the ‘A’ conformation have considerably more bridging sites in this low hydration form than in the ‘B’ conformation. Sequence related solvent effects for a given conformation have also been analysed.     

Allocation, plasticity and allometry in plants

Allocation is one of the central concepts in modern ecology, providing the basis for different strategies. Allocation in plants has been conceptualized as a proportional or ratio-driven process (‘partitioning’). In this view, a plant has a given amount of resources at any point in time and it allocates these resources to different structures. But many plant ecological processes are better understood in terms of growth and size than in terms of time. In an allometric perspective, allocation is seen as a size-dependent process: allometry is the quantitative relationship between growth and allocation. Therefore most questions of allocation should be posed allometrically, not as ratios or proportions. Plants evolve allometric patterns in response to numerous selection pressures and constraints, and these patterns explain many behaviours of plant populations.

In the allometric view, plasticity in allocation can be understood as a change in a plant's allometric trajectory in response to the environment. Some allocation patterns show relatively fixed allometric trajectories, varying in different environments primarily in the speed at which the trajectory is travelled, whereas other allocation patterns show great flexibility in their behaviour at a given size. Because plant growth is often indeterminate and its rate highly influenced by environmental conditions, ‘plasticity in size’ is not a meaningful concept. We need a new way to classify, describe and analyze plant allocation and plasticity because the concepts ‘trait’ and ‘plasticity’ are too broad. Three degrees of plasticity can be distinguished: (1) allometric growth (‘apparent plasticity’), (2) modular proliferation and local physiological adaptation, and (3) integrated plastic responses. Plasticity, which has evolved because it increases individual fitness, can be a disadvantage in plant production systems, where we want to optimize population, not individual, performance.     

Application of CP-MAS and liquid-like solid-state NMR experiments for the study of the ripening-associated cell wall changes in tomato

¹³C and ¹H NMR spectra of an ethanol insoluble material (EIM) prepared from the pericarp of mature-green (MG) and red-ripe (RR) tomato fruits were acquired in ‘liquid-like’ and cross-polarisation with dipolar decoupling and magic angle spinning (CPMAS) conditions using the same triple resonance probe. Such a strategy allowed acquisitions of various NMR experiments aimed at detecting compositional differences as well as distinguishing differences in molecular mobility for various constituent polysaccharides related with the two ripening stages. Increase of the proton dipolar decoupling power levels from 3 to 50–55 kHz during single pulse ¹³C acquisition, led to more intense signals for pectic and hemicellulosic polysaccharides. This behaviour was interpreted as reflecting motional restrictions of these polysaccharides inside the porous cell wall network. Measurements of the proton rotating frame relaxation times T_1ρ in the ‘liquid-like’ conditions and of the proton transverse relaxation times T₂ from CPMAS spectra, revealed changes in mobilities for some pectic polysaccharides in relation with ripening, particularly for the H1 and H5 protons of -1,5 arabinan (Ara) side chains of rhamnogalacturonans. These data are discussed in relation with known pectic modifications occurring during ripening and associated with the tomato fruit softening.     

A physico-chemical study on the polysaccharide ulvan from hot water extraction of the macroalga Ulva.

Results of a study on the solution behaviour of the cell-wall polysaccharide named ulvan obtained from hot water extraction of a flour of Ulva ‘rigida’ are reported. In particular the spectroscopic properties and ion binding capacity of this charged polysaccharide were studied by circular dichroism and isothermal microcalorimetric titrations in order to gain information on the potential exploitation of this low cost biomass. A marked tendency of this polysaccharide to uptake water was evidenced by studying the proton spin-lattice relaxation times of the solvent, T₁, embedded in this highly charged polysaccharide.     

Changes in ecdysone titre during pupal-adult development in the silkworm, Bombyx mori

Changes in the ecdysone titre of the silkworm, Bombyx mori, during pupal-adult development were estimated. The average value of the maximum titre, which was observed on the second day after pupal ecdysis, was about 0·8 μg equivalent of β-ecdysone/g of live weight in both sexes.

There is a distinct sexual dimorphism in the pattern of the ecdysone titre. The male exhibited a single sharp peak on the second day whereas the female showed the second peak on the fifth day. When the female was ovariectomized, the ‘female type’ ecdysone pattern was converted to the ‘male type’. In the female pharate adult 7 days after pupal ecdysis, ecdysone activity accumulated in the ovaries.

The relationship between the ecdysone titre and adult differentiation, especially during ovarian development, is discussed.     

Selective delta-opioid receptor antagonism by ICI 174,864 in the central nervous system

The effects of the novel gamma-opioid receptor antagonist ICI 174,864 (N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH: Aib = alpha-aminoisobutyric acid) have been examined in the CNS in vivo using spontaneous reflex contractions of the rat urinary bladder as an index of activity. Bladder contractions were inhibited by equipotent intracerebroventricular (ICV) doses of the selective mu-agonist DAGO [D-Ala2, MePhe4,Gly-(ol)5]enkephalin and the delta-agonist DPDPE[D-Pen2, D-Pen5]enkephalin. ICI 174,864 (1-3 micrograms) administered by the same route produce a selective and reversible antagonism of DPDPE effects. At higher doses (6-15 micrograms, ICV) ICI 174,864 exhibited marked agonistic activity, producing inhibition of bladder contractions that were resistant to ICV naloxone (1-2 micrograms). Thus ICI 174,864 was considered a selective central delta-opioid receptor antagonist but its usefulness was limited by additional agonistic properties.     

Transitions between cooperative and non-cooperative responding in the 'Pigeon's Dilemma'

Two pigeons played Iterated Prisoner's Dilemma (IPD) against a simulated opponent pre-programmed to play ‘Tit-For-Tat’ (TFT) and ‘Random’ (RND) strategies. Each pigeon received differential amounts of access to food following choices of either ‘cooperate’ or ‘defect’ on a trial. After 1000 trials against TFT and 500 trials against RND, results indicated that choice allocation was optimal when the birds played against RND but was sub-optimal when the birds played against TFT. In order to determine why the pigeons responded suboptimally against TFT, a trial-by-trial analysis of the data was conducted. The analysis revealed that once a pigeon had received the ‘Sucker's’ payoff (S), it was more likely to defect and receive the ‘Temptation’ payoff (T) than to cooperate and receive the ‘Reward’ (R) payoff. Local reinforcement contingencies appear to determine suboptimal responding against TFT in the iterated Pigeon's Dilemma.     

Stimulation of afferent vagal endings in the intrapulmonary airways by prostaglandin endoperoxide analogues

Two cyclic ether (CE) analogues of the prostaglandin endoperoxide PGH₂, CE I and CE II, have been found to exert powerful stimulant effects on lung ‘irritant’ receptors and bronchial C-fiber endings after intravascular or aerosol administration in open-chest dogs under Dial-pentobarbital anesthesia. ‘Irritant’ receptors responded to a dose as small as 0.1 μg/kg CE II, injected into the right atrium. CE II was twice as effective as CE I and 10–20 times more potent than PGF_2α. As an aerosol, it exceeded histamine in potency by more than 800 times. ‘Irritant’ receptor stimulation was always associated with decrease in lung compliance and increase in lung resistance. Isoproterenol which reduced the latter effects also diminished the response of ‘irritant’ receptors. Left atrial injection of GE_S had only weak and delayed effects. CE-induced ‘irritant’ receptor firing declined or ceased during ventilatory arrest in expiration and following hyperinflation of the lungs. In contrast to ‘irritant’ receptors, C-fibers responded more effectively and more rapidly, and in the absence of mechanical changes, when the drugs were injected into the left atrium as compared to right atrial injection. These findings suggest that CE-induced ‘irritant’ receptor stimulation is secondary to changes in lung mechanics, whereas C-fiber stimulation is a direct effect upon the nerve ending.