Concept: Barber's pole
SUMMARY Ivermectin (IVE), one of the most important anthelmintics, is often used in the treatment of haemonchosis in ruminants. The objective of our work was (1) to find and identify phase I and II metabolites of IVE formed by the Barber’s pole worm (Haemonchus contortus), and (2) to compare IVE metabolites in helminths with IVE biotransformation in sheep (Ovis aries) as host species. Ultrahigh-performance liquid chromatography/tandem mass spectrometry (UHPLC/MS/MS) was used for this purpose. During in vitro incubations, microsomes (from adult worms or from ovine liver) and a primary culture of ovine hepatocytes were incubated with IVE. In the ex vivo study, living H. contortus adults were incubated in the presence of 1 μM IVE for 24 h. The results showed that the H. contortus enzymatic system is not able to metabolize IVE. On the other hand, 7 different phase I as well as 9 phase II IVE metabolites were detected in ovine samples using UHPLC/MS/MS analyses. Most of these metabolites have not been described before. Haemonchus contortus is not able to deactivate IVE through biotransformation; therefore, biotransformation does not contribute to the development of IVE-resistance in the Barber’s pole worm.
Haemonchus contortus (Barber’s pole worm or “BPW”) is the nematode “nemesis” of small ruminant production systems in tropical and subtropical regions of the world. Its reputation derives from a combination of high fecundity and a short generational interval that provides an enviable developmental plasticity for adaptation or resistance to control measures. This review critically examines the historical and current literature on the host-parasite-environment (HPE) interaction for H. contortus, particularly in sheep, to highlight changes in parasite distribution and ecology on pasture, changes to the seasonal inhibition of fourth stage larvae and the most appropriate models to identify protective responses and assess vaccines. The review also proposes pathways to bring host genetics to fruition and avenues where advances in the parasite genome may complement control measures.
In this study, we tested five series of pyrazole-5-carboxamide compounds (n = 55) for activity against parasitic stages of the nematode Haemonchus contortus (barber’s pole worm), one of the most pathogenic parasites of ruminants.
Albendazole in environment: faecal concentrations in lambs and impact on lower development stages of helminths and seed germination
- Environmental science and pollution research international
- Published over 1 year ago
Albendazole (ABZ), widely used benzimidazole anthelmintic, administered to animals enters via excrements into environment and may impact non-target organisms. Moreover, exposure of lower development stages of helminths to anthelmintics may also encourage the development of drug-resistant strains of helminths. In present project, the kinetics of ABZ (10 mg kg(-1) p.o.) and its metabolite (ABZ.SO, ABZSO2) elimination in faeces from treated Texel lambs were studied using UHPLC/MS/MS with the aim to find out their concentrations achievable in the environment. Consequently, the effect of these compounds on lower development stages of Barber’s pole worm (Haemonchus contortus) and on germination of white mustard (Sinapis alba) seeds was evaluated. The results showed that ABZ concentrations in faeces excreted in 4-60 h after treatment were above the concentrations lethal for H. contortus eggs. Moreover, pre-incubation with sub-lethal doses of ABZ and ABZ.SO did not increase the resistance of H. contortus eggs and larvae to anthelmintics. On the other hand, concentrations of ABZ and ABZ.SO in faeces are so high that might have negative influence on non-target soil invertebrates. As neither ABZ nor its metabolites affect the germination of mustard seeds, phytoremediation could be considered as potential tool for detoxification of ABZ in the environment.
N-glycans from the nematode Haemonchus contortus (barber pole worm), a parasite of sheep and cattle, were the first to be described to possess up to three fucose residues associated with the N,N'-diacetylchitobiosyl core, two being on the reducing-terminal proximal GlcNAc and one on the distal core GlcNAc residue. The assumption was that truncated glycans from this organism with three hexose residues have the composition Man3GlcNAc2Fuc1-3. In this study we have performed HPLC and MALDI-TOF MS/MS in combination with selected digestions of N-glycans from Haemonchus. A dominant trifucosylated Hex3HexNAc2Fuc3 glycan was modified not only with α1,6-fucose, but also with a proximal core α1,3-fucose and a galactosylated distal α1,3-fucose; thereby, only two of the hexose residues were mannose. Other N-glycans displayed galactosylation of the core α1,6-fucose, antennal fucosylation or modification with phosphorylcholine. Thus, the N-glycans of Haemonchus contain a number of potentially immunogenic glycan epitopes also found in other parasites and our proposed structures are in line with the previously-defined specificity of nematode glycosyltransferases as we show distal fucosylation and the presence of an α1,6-mannose are apparently mutually exclusive. These data are thereby of importance for engineering cell lines capable of mimicking Haemonchus-type N-glycans in the preparation of recombinant proteins as vaccine candidates.
Due to major problems with drug resistance in parasitic nematodes of animals, there is a substantial need and excellent opportunities to develop new anthelmintics via genomic-guided and/or repurposing approaches. In the present study, we established a practical and cost-effective whole-organism assay for the in vitro-screening of compounds for activity against parasitic stages of the nematode Haemonchus contortus (barber’s pole worm). The assay is based on the use of exsheathed L3 (xL3) and L4 stages of H. contortus of small ruminants (sheep and goats). Using this assay, we screened a panel of 522 well-curated kinase inhibitors (GlaxoSmithKline (GSK), USA; code: PKIS2) for activity against H. contortus by measuring the inhibition of larval motility using an automated image analysis system. We identified two chemicals within the compound classes biphenyl amides and pyrazolo[1,5-α]pyridines, which reproducibly inhibit both xL3 and L4 motility and development, with IC50s of 14 - 47 μM. Given that these inhibitors were designed as anti-inflammatory drugs for use in humans and fit the Lipinski rule-of-five (including bioavailability), they show promise for hit-to-lead optimisation and repurposing for use against parasitic nematodes. The screening assay established here has significant advantages over conventional methods, particularly in terms of ease of use, throughput, time and cost. Although not yet fully automated, the current assay is readily suited to the screening of hundreds to thousands of compounds for subsequent hit-to-lead optimisation. The current assay is highly adaptable to many parasites of socioeconomic importance, including those causing neglected tropical diseases. This aspect is of major relevance, given the urgent need to deliver the goals of the London Declaration (http://unitingtocombatntds.org/resource/london-declaration) through the rapid and efficient repurposing of compounds in public-private partnerships.
Parasitic worm proteins that belong to the cysteine-rich secretory proteins, antigen 5 and pathogenesis-related 1 (CAP) superfamily are proposed to play key roles in the infection process and the modulation of immune responses in host animals. However, there is limited information on these proteins for most socio-economically important worms. Here, we review the CAP protein superfamily of Haemonchus contortus (barber’s pole worm), a highly significant parasitic roundworm (order Strongylida) of small ruminants. To do this, we mined genome and transcriptomic datasets, predicted and curated full-length amino acid sequences (n=45), undertook systematic phylogenetic analyses of these data and investigated transcription throughout the life cycle of H. contortus. We inferred functions for selected C. elegans orthologs (including vap-1, vap-2, scl-5 and lon-1) based on genetic networking and by integrating data and published information, and were able to infer that a subset of orthologs and their interaction partners play pivotal roles in growth and development via the insulin-like and/or the TGF-beta signaling pathways. The identification of the important and conserved growth regulator LON-1 led us to appraise the three-dimensional structure of this CAP protein by comparative modelling. This model revealed the presence of different topological moieties on the canonical fold of the CAP domain, which coincide with an overall charge separation as indicated by the electrostatic surface potential map. These observations suggest the existence of separate sites for effector binding and receptor interactions, and thus support the proposal that these worm molecules act in similar ways as venoms act as ligands for chemokine receptors or G protein-coupled receptor effectors. In conclusion, this review should guide future molecular studies of these molecules, and could support the development of novel interventions against haemonchosis.
In the Barber-Pole Illusion (BPI), a diagonally moving grating is perceived as moving vertically because of the narrow, vertical, rectangular shape of the window through which it is viewed. This strong shape-motion interaction persists through a wide range of parametric variations in the shape of the window, the spatial and temporal frequencies of the moving grating, the contrast of the moving grating, complex variations in the composition of the grating and window shape, and the duration of viewing. It is widely believed that end-stop-feature (third-order) motion computations determine the BPI, and that Fourier motion-energy (first-order) computations determine failures of the BPI. Here we show that the BPI is more complex: (1) In a wide variety of conditions, weak-feature stimuli (extremely fast, low contrast gratings, 21.5 Hz, 4% contrast) that stimulate only the Fourier (first-order) motion system actually produce a slightly better BPI illusion than classical strong-feature gratings (2.75 Hz, 32% contrast). (2) Reverse-phi barberpole stimuli are seen exclusively in the forward (feature, third-order) BPI direction when presented at 2.75 Hz and exclusively in the opposite (Fourier, first-order) BPI direction at 21.5 Hz. (3) The BPI in barber poles with scalloped edges (Badcock, McKendrick, and Ma-Wyatt, VisRes, 2003) is much weaker than in normal straight-edge barber poles for 2.75 Hz stimuli but not in 21.5 Hz stimuli.
Pharmacokinetics and anthelmintic activity of topical eprinomectin in goats prevented from physical contact to others and self-grooming were studied. Sixteen approximately 7 months old male castrated German White Noble goats harbouring induced infections of gastrointestinal nematode parasites were included in the study. They were blocked based on pre-treatment body weight (range 22.4 to 36.4 kg) and then randomly allocated to the untreated control group or the group treated with topical 0.5 % w/v eprinomectin (EPRINEX® Pour-on, Merial) at 1 mg/kg body weight. Plasma samples were collected prior to and at intervals up to 14 days following treatment and analyzed to determine the concentrations of eprinomectin (B1a component). Parasites were recovered, identified, and counted following necropsy 14 days after treatment. Goats treated with topical eprinomectin had significantly fewer (≥99 % reduction, p < 0.01) adult Cooperia curticei, Haemonchus contortus, Nematodirus battus, Oesophagostomum venulosum, Ostertagia circumcincta, and Trichostrongylus colubriformis than the untreated controls. Basic pharmacokinetic parameters for eprinomectin B1a were AUCinfinity, 37.1 ± 15.2 day ng/mL; T½, 5.11 ± 2.83 days; and Cmax, 5.93 ± 1.87 ng/mL; individual maximal concentrations were observed 1 or 2 days after treatment. Results of this study indicate that oral ingestion is not required to achieve adequate exposure for excellent anthelmintic efficacy following topical administration of eprinomectin at 1 mg/kg body weight to goats.
How is motion information that has been obtained through multiple viewing apertures integrated to form a global motion percept? We investigated the mechanisms of motion integration across apertures in two hemifields by presenting gratings through two rectangles (that form the dual barber poles) and recording the perceived direction of motion by human observers. To this end, we presented dual barber poles in conditions with various inter-component distances between the apertures and evaluated the degree to which the hemifield information was integrated by measuring the magnitude of the perceived barber pole illusion. Surprisingly, when the inter-component distance between the two apertures was short, the perceived direction of motion of the dual barber poles was similar to that of a single barber pole formed by the concatenation of the two component barber poles, indicating motion integration is achieved through a simple concatenation mechanism. We then presented dual barber poles in which the motion and contour properties of the two component barber poles differed to characterize the constraints underlying cross-hemifield integration. We found that integration is achieved only when phase, speed, wavelength, temporal frequency, and duty cycle are identical in the two barber poles, but can remain robust when the contrast of the two component barber poles differs substantially. We concluded that a motion stimulus presented in bilateral hemifields tends to be integrated to yield a global percept with a substantial tolerance for spatial distance and contrast difference.