When given to sheep as a single oral dose at 0.1 mg/kg, the Bia component of the avermectins caused a reduction of >95% in the numbers of Haemonchus contortus, Ostertagia circumcincta (including inhibited L4 larvae), Tricho- Fermentation-derived natural products which are attributed with anthelmintic activity have been described in the literature. Hygromycin B, which has been used in treating domestic animals in practice, was described in 1958 (8). It was shown to have some effect upon adult swine ascarids when fed to infected pigs (7) but found ineffective against the migrating larvae of Ascaris suum (6). The principal utility of hygromycin B appears directed against members of the nematode order Ascaroidea. In this paper we report the anthelmintic activity of a natural product, the B18 component of the avermectins (3, 9), an a-L-oleandrosyl-a-L-oleandroside macrocyclic lactone, against nematode parasites of cattle, sheep, dogs, and chickens.MATERIALS AND METHODS Sheep. Sheep raised under "parasite-free" conditions (i.e., management conditions designed to ensure minimal exposure to helminth infection) and weighing between 14 and 25 kg at the time of treatment were experimentally infected with third-stage infective larvae of six nematode species, passaged in the laboratory as pure isolates, according to the following: day 0, 360 Oesophagostomum columbianum; day 16, 7,500 Ostertagia circumcincta and 7,500 Trichostrongylus colubriformis; day 18, 7,500 Trichostrongylus axei and 7,500 Cooperia oncophora; day 21, 2,000 Haemonchus contortus. The isolates of T. colubriformis and H. contortus used to infect sheep were tolerant to benzimidazole anthelmintic treatment, requiring more than the recommended use level of various benzimidazoles for high-order efficacy. Numbers of larvae were estimated by counting multiple samples of larval suspensions in tap water, and each animal was infected per os with 5 ml of larval suspension containing the desired number.On day 35, when the infections were patent, 15 infected sheep were randomly allotted to five treatment groups of three sheep each. The groups were randomly allotted to infected control (no treatment, two groups) or treatment with avermectin B,I at 0.

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Ion flow in many voltage-gated K؉ channels (VGK), including the (human ether-a-go-go-related gene) hERG channel, is regulated by reversible collapse of the selectivity filter. hERG channels, however, exhibit low sequence homology to other VGKs, particularly in the outer pore helix (S5) domain, and we hypothesize that this contributes to the unique activation and inactivation kinetics in hERG K ؉ channels that are so important for cardiac electrical activity. The S5 domain in hERG identified by NMR spectroscopy closely corresponded to the segment predicted by bioinformatics analysis of 676 members of the VGK superfamily. Mutations to approximately every third residue, from Phe 551 to Trp 563 , affected steady state activation, whereas mutations to approximately every third residue on an adjacent face and spanning the entire S5 segment perturbed inactivation, suggesting that the whole span of S5 experiences a rearrangement associated with inactivation. We refined a homology model of the hERG pore domain using constraints from the mutagenesis data with residues affecting inactivation pointing in toward S6. In this model the three residues with maximum impact on activation (W563A, F559A, and F551A) face out toward the voltage sensor. In addition, the residues that when mutated to alanine, or from alanine to valine, that did not express (Ala 561 , His 562 , Ala 565 , Trp 568 , and Ile 571 ), all point toward the pore helix and contribute to close hydrophobic packing in this region of the channel.

Understanding the pharmacological similarity of G protein-coupled receptors (GPCRs) is paramount to predicting ligand off-target effects, drug repurposing, and ligand discovery for orphan receptors. Phylogenetic relationships do not always correctly capture pharmacological similarity. Previous family-wide attempts to define pharmacological relationships were based on three-dimensional structures and/or known receptor:ligand pairings, both unavailable for orphan GPCRs. Here, we present GPCR-CoINPocket, a novel contact-informed neighboring pocket metric of GPCR binding site similarity that is informed by patterns of ligand:residue interactions observed in crystallographically-characterized GPCRs. GPCR-CoINPocket is applicable to receptors with unknown structure or ligands and accurately captures known pharmacological relationships between GPCRs, even those undetected by phylogeny. When applied to orphan receptor GPR37L1, GPCR-CoINPocket identified its pharmacological neighbors, and transfer of their pharmacology aided discovery of the first surrogate ligands for this orphan with a 30% success rate. Although primarily designed for GPCRs, the method is easily transferable to other protein families.

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Babesia argeutina, a protozoan parasite causing tick fever of cattle in Australia, is transmitted by Boophilus microplus. Its development in this invertebrate vector is very similar to that recorded by Riek (1964) for Babesia bigemina. Many of the parasites occurring in the bovine erythrocytes are destroyed on ingestion but the early development in the lumen of the gut is uncertain. By about 36 hr, blunt, cigar-shaped forms, 7.2–1 3.8 µ by 2.6–5.6 µ, invade the epithelial cells of the gut and subsequent development is by means of multiple fission. This leads, by about 96 hr, to the production of mature vermicules which measure about 15.8 µ by 3.0 µ, with a range of 14.3–16.9 µ by 2.8–3.5 µ. At about this time vermicules enter the mature ova of the tick, and a further cycle of multiple fission in the gut cells of the developing larva gives rise to vermicules similar to those produced in the adult tick. The final cycle takes place in the salivary glands of the larva, and the forms infective to the vertebrate host appear 2–3 days and longer after larval attachment. Multiplication in this cycle is also by multiple fission and gives rise to comparatively small numbers of infective forms measuring about 1.5 µ by 1.0 µ. Not all ticks develop an infection even after engorging on blood with a high parasite density. Certain 'strains' of Boophilus microplus seem to be more susceptible to infection than others. Heavy mortalities occurred in many ticks after ingesting blood with a parasite density of 5% or higher.