Inbreeding in artificial selection programmes.

In a population under artificial selection, the effective population size may be less than the actual number of parents selected because there will be variation between families in the character under selection and consequently in the probability of selection. Expressions are developed for the magnitude of the effect, which will be greater the more intense the selection and the higher the heritability of the selected character. The inbreeding due to outstanding individuals may rise for several generations after their use

Secretly Eccentric: The Giant Planet and Activity Cycle of GJ 328

We announce the discovery of a ~2 Jupiter-mass planet in an eccentric 11-year orbit around the K7/M0 dwarf GJ 328. Our result is based on 10 years' worth of radial velocity (RV) data from the Hobby-Eberly and Harlan J. Smith telescopes at McDonald Observatory, and from the Keck Telescope at Mauna Kea. Our analysis of GJ 328's magnetic activity via the Na I D features reveals a long-period stellar activity cycle, which creates an additional signal in the star's RV curve with amplitude 6-10 m/s. After correcting for this stellar RV contribution, we see that the orbit of the planet is more eccentric than suggested by the raw RV data. GJ 328b is currently the most massive, longest-period planet discovered around a low-mass dwarf.Comment: Accepted for publication in Ap

Functional expression of a glutamate-gated chloride channel (GLC-3) from adult Brugia malayi.

Parasitic worms are causative agents for six highly prevalent neglected tropical diseases of humans which include ascariasis, lymphatic filariasis, schistosomiasis, trichuriasis, hookworm infection, and onchocerciasis that affect a high percentage of the world’s population. Resistance to available anthelminthic drugs especially for the benzimidazole anthelmintic agents (e.g., albendazole and mebendazole) and ivermectin is a serious concern (this is a real problem for veterinary medicine and a growing concern in human medicine). Previous studies involving ivermectin have shown that it has a limited action against adult filarial worms. Here, we describe the functional expression of a glutamate-gated chloride channel (GLC-3) from adult Brugia malayi, a filarial parasite. We expressed GLC-3 in Xenopus laevis oocytes and used two-electrode voltage-clamp electrophysiology to study the resulting ion channel. Application of various receptor agonists (1 mM): L-aspartate, glycine, γ-aminobutyric acid (GABA), α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) failed to activate the GLC3 receptor. Application of 1mM L-glutamate and ibotenate produced robust inward currents. Further experiments revealed that GLC-3 is a glutamate-gated channel with an EC50 of 64.8 4.01 µM and a Hill coefficient of 2.56 0.46 µM. We recorded the responses to 300 µM L-glutamate over a range of holding potentials (-80 to +20 mV) and constructed a current-voltage plot. The current-voltage relationship revealed a reversal potential (Erev) of -35.3 3.2 mV indicating the GLC-3 channel is selective for chloride ions. The GluCl channel antagonists picrotoxin and fipronil had negligible inhibitory effects on the L-glutamate responses. We investigated the ivermectin effects on the GLC-3 receptor which reveals ivermectin to be an agonist with an EC50 of 3.6 nM (pEC50 = -2.4 ± 0.4). Interestingly, we also observed that Ivermectin has an inhibitory effect on the GLC-3 glutamate response at very low concentrations, IC50 = 73 pM (pIC50 = -4.1 ± 11.4). This is in stark contrast to the previously reported positive allosteric (PAM) effects of ivermectin on many invertebrate GluCls

Pharmacological receptors of nematoda as target points for action of antiparasitic drugs

Cholinergic receptors of parasitic nematodes are one of the most important possible sites of action of antiparasitic drugs. This paper presents some of our own results of electrophysiological and pharamcological examinations of nicotinic and muscarinic receptors of nematodes, as well as data from literature on a new class of anthelmintics that act precisely on cholinergic receptors. The nicotinic acetylcholine receptor (nAChR) is located on somatic muscle cells of nematodes and it is responsible for the coordination of parasite movement. Cholinomimetic anthelmintics act on this receptor, as well as acetylcholine, an endogenic neurotransmitter, but they are not sensitive to enzyme acetylcholineesterase which dissolves acetylcholine. As opposed to the nicotinic receptor of vertebra, whose structure has been examined thoroughly, the stoichiometry of the nicotinic receptor of nematodes is not completely known. However, on the grounds of knowledge acquired so far, a model has been constructed recently of the potential composition of a type of nematodes nicotinic receptor, as the site of action of anthelmintics. Based on earlier investigations, it is supposed that a conventional muscarinic receptor exists in nematodes as well, so that it can also be a new pharamocological target for the development of antinematode drugs. The latest class of synthesized anthelmintics, named aminoacetonitriles (AAD), act via the nicotinic receptor. Monepantel is the first drug from the AAD group as a most significant candidate for registration in veterinary medicine. Even though several groups of cholinomimetic anthelmintics (imiodazothiazoles, tetrahydropyrimidines, organophosphat anthelmintics) have been in use in veterinary practice for many years now, it is evident that cholinergic receptors of nematodes still present an attractive place in the examinations and development of new antinematode drugs.

Functional Characterization of a Novel Family of Acetylcholine-Gated Chloride Channels in Schistosoma mansoni

Acetylcholine is the canonical excitatory neurotransmitter of the mammalian neuromuscular system. However, in the trematode parasite Schistosoma mansoni, cholinergic stimulation leads to muscle relaxation and a flaccid paralysis, suggesting an inhibitory mode of action. Information about the pharmacological mechanism of this inhibition is lacking. Here, we used a combination of techniques to assess the role of cholinergic receptors in schistosome motor function. The neuromuscular effects of acetylcholine are typically mediated by gated cation channels of the nicotinic receptor (nAChR) family. Bioinformatics analyses identified numerous nAChR subunits in the S. mansoni genome but, interestingly, nearly half of these subunits carried a motif normally associated with chloride-selectivity. These putative schistosome acetylcholine-gated chloride channels (SmACCs) are evolutionarily divergent from those of nematodes and form a unique clade within the larger family of nAChRs. Pharmacological and RNA interference (RNAi) behavioral screens were used to assess the role of the SmACCs in larval motor function. Treatment with antagonists produced the same effect as RNAi suppression of SmACCs; both led to a hypermotile phenotype consistent with abrogation of an inhibitory neuromuscular mediator. Antibodies were then generated against two of the SmACCs for use in immunolocalization studies. SmACC-1 and SmACC-2 localize to regions of the peripheral nervous system that innervate the body wall muscles, yet neither appears to be expressed directly on the musculature. One gene, SmACC-1, was expressed in HEK-293 cells and characterized using an iodide flux assay. The results indicate that SmACC-1 formed a functional homomeric chloride channel and was activated selectively by a panel of cholinergic agonists. The results described in this study identify a novel clade of nicotinic chloride channels that act as inhibitory modulators of schistosome neuromuscular function. Additionally, the iodide flux assay used to characterize SmACC-1 represents a new high-throughput tool for drug screening against these unique parasite ion channels

Book Reviews

Book Review 1Book Title: Megaherbivores: the influence of very large body size on ecologyBook Author: R.N. Owen-SmithCambridge University Press, Cambridge, 1988. 369 pages.Book Review 2Book Title: Comparative Physiology of the Vertebrate KidneyBook Author: W.H. Dantzler Springer-Verlag 1989.198 pp. (Hardcover).Book Review 3Book Title: Atlas on the Biology of Soil ArthropodsBook Authors: G. Esenbeis & W. Wichard Springer-Verlag, Berlin 1987. 437 pp.Book Review 4Book Title: Primate Vocal CommunicationBook Authors: Edited by D. Todt, P. Goedeking & D. SymmesSpringer Verlag, Berlin (1988)Book Review 5Book Title: The Honey BeeBook Authors: J.L. Gould & C. G. GouldScientific American Ubrary, W.H.Freeman, New York. 239 pp.Book Review 6Book Title: Insect Development Photoperiodic and Temperature ControlBook Author: Victor A. ZaslavskiSpringer-Verlag, Berlin. 187 pp.Book Review 7Book Title: OrganellesBook Author: Mark CarrollMacmillan 1989. 202 pp.Book Review 8Book Title: Comparative Protozoology Ecology, Physiology, Life HistoryBook Author: O. Roger AndersonSpringer-Verlag, Berlin, 1988. 482pp.Book Review 9Book Title: Ecotoxicology: Problems and ApproachesBook Authors: Edited by S.A. Levin, M.A. Harwell, J.R. Kelly & K.D. KimballSpringer Verlag, New York. 547 pp

Monepantel is a non-competitive antagonist of nicotinic acetylcholine receptors from Ascaris suum and Oesophagostomum dentatum

Zolvix (R) is a recently introduced anthelmintic drench containing monepantel as the active ingredient. Monepantel is a positive allosteric modulator of DEG-3/DES-2 type nicotinic acetylcholine receptors (nAChRs) in several nematode species. The drug has been reported to produce hypercontraction of Caenorhabditis elegans and Haemonchus contortus somatic muscle. We investigated the effects of monepantel on nAChRs from Ascaris suum and Oesophagostomum dentatum heterologously expressed in Xenopus laevis oocytes. Using two-electrode voltagec-lamp electrophysiology, we studied the effects of monepantel on a nicotine preferring homomeric nAChR subtype from A. suum comprising of ACR-16; a pyrantel/tribendimidine preferring heteromeric subtype from O. dentatum comprising UNC-29, UNC-38 and UNC-63 subunits; and a levamisole preferring subtype (O. dentatum) comprising UNC-29, UNC-38, UNC-63 and ACR-8 subunits. For each subtype tested, monepantel applied in isolation produced no measurable currents thereby ruling out an agonist action. When monepantel was continuously applied, it reduced the amplitude of acetylcholine induced currents in a concentration-dependent manner. In all three subtypes, monepantel acted as a non-competitive antagonist on the expressed receptors. ACR-16 from A. suum was particularly sensitive to monepantel inhibition (IC50 values: 1.6 +/- 3.1 nM and 0.2 +/- 2.3 mu M). We also investigated the effects of monepantel on muscle flaps isolated from adult A. suum. The drug did not significantly increase baseline tension when applied on its own. As with acetylcholine induced currents in the heterologously expressed receptors, contractions induced by acetylcholine were antagonized by monepantel. Further investigation revealed that the inhibition was a mixture of competitive and non-competitive antagonism. Our findings suggest that monepantel is active on multiple nAChR subtypes

Male frequent attenders of general practice and their help seeking preferences

Background: Low rates of health service usage by men are commonly linked to masculine values and traditional male gender roles. However, not all men conform to these stereotypical notions of masculinity, with some men choosing to attend health services on a frequent basis, for a variety of different reasons. This study draws upon the accounts of male frequent attenders of the General Practitioner's (GP) surgery, examining their help-seeking preferences and their reasons for choosing services within general practice over other sources of support. Methods: The study extends thematic analysis of interview data from the Self Care in Primary Care study (SCinPC), a large scale multi-method evaluation study of a self care programme delivered to frequent attenders of general practice. Data were collected from 34 semi-structured interviews conducted with men prior to their exposure to the intervention. Results: The ages of interviewed men ranged from 16 to 72 years, and 91% of the sample (n= 31) stated that they had a current health condition. The thematic analysis exposed diverse perspectives within male help-seeking preferences and the decision-making behind men's choice of services. The study also draws attention to the large variation in men's knowledge of available health services, particularly alternatives to general practice. Furthermore, the data revealed some men's lack of confidence in existing alternatives to general practice. Conclusions: The study highlights the complex nature of male help-seeking preferences, and provides evidence that there should be no 'one size fits all' approach to male service provision. It also provides impetus for conducting further studies into this under researched area of interest. © 2011 WPMH GmbH