The cytochrome P450 family in the parasitic nematode <i>Haemonchus contortus</i>

&lt;i&gt;Haemonchus contortus&lt;/i&gt;, a highly pathogenic and economically important parasitic nematode of sheep, is particularly adept at developing resistance to the anthelmintic drugs used in its treatment and control. The basis of anthelmintic resistance is poorly understood for many commonly used drugs with most research being focused on mechanisms involving drug targets or drug efflux. Altered or increased drug metabolism is a possible mechanism that has yet to receive much attention despite the clear role of xenobiotic metabolism in pesticide resistance in insects. The cytochrome P450s (CYPs) are a large family of drug-metabolising enzymes present in almost all living organisms, but for many years thought to be absent from parasitic nematodes. In this paper, we describe the CYP sequences encoded in the &lt;i&gt;H. Contortus&lt;/i&gt; genome and compare their expression in different parasite life-stages, sexes and tissues. We developed a novel real-time PCR approach based on partially assembled CYP sequences “tags” and confirmed findings in the subsequent draft genome with RNA-seq. Constitutive expression was highest in larval stages for the majority of CYPs, although higher expression was detected in the adult male or female for a small subset of genes. Many CYPs were expressed in the worm intestine. A number of &lt;i&gt;H. Contortus&lt;/i&gt; genes share high identity with &lt;i&gt;Caenorhabditis elegans&lt;/i&gt; CYPs and the similarity in their expression profiles supports their classification as putative orthologues. Notably, &lt;i&gt;H. Contortus&lt;/i&gt; appears to lack the dramatic CYP subfamily expansions seen in &lt;i&gt;C. elegans&lt;/i&gt; and other species, which are typical of CYPs with exogenous roles. However, a small group of &lt;i&gt;H. Contortus&lt;/i&gt; genes cluster with the &lt;i&gt;C. elegans&lt;/i&gt; CYP34 and CYP35 subfamilies and may represent candidate xenobiotic metabolising genes in the parasite

Socioeconomic deprivation as measured by the index of multiple deprivation and its association with low sex hormone binding globulin in women

ACKNOWLEDGEMENTS M.L., I.L. and A.H.H. participated in the study concept and design, acquisition of data, study analysis, interpretation of data, drafting of the manuscript. D.M. provided statistical expertise. R.D., A.J.H., and A.F. participated in the interpretation of data and critical revision of the manuscript.Peer reviewedPublisher PD

Radio Jet-Ambient Medium Interactions on Parsec Scales in the Blazar 1055+018

As part of our study of the magnetic fields of AGN we have recently observed a large sample of blazars with the Very Long Baseline Array. Here we report the discovery of a striking two-component jet in the source 1055+018, consisting of an inner spine with a transverse magnetic field, and a fragmentary but distinct boundary layer with a longitudinal magnetic field. The polarization distribution in the spine strongly supports shocked-jet models while that in the boundary layer suggests interaction with the surrounding medium. This behavior suggests a new way to understand the differing polarization properties of strong- and weak-lined blazars.Comment: LaTex; 10 pages; 6 figures; reference fix; to appear in ApJL, 518, 1999 June 2

Using movement, diet, and genetic analyses to understand Arctic charr responses to ecosystem change

ACKNOWLEDGEMENTS The extensive datasets used in this study were reliant on the dedication and innovation of many residents of Nunatsiavut (Food Skills and Environmental Research Program), technicians and biologists from DFO (J. Seiden, D. Lancaster, M. Shears, M. Bloom, S. Duffy), the Nunatsiavut Government (P. McCarney, C. Andersen, L. Pijogge), Oceans North (S. Pain), and of the captains and crew of the What’s Happening and the Safe Passage. Suggestions by three anonymous reviewers also greatly improved the manuscript. Funding for this research was provided in part by ArcticNet and DFO Oceans.Peer reviewedPublisher PD

An optical-IR jet in 3C133

We report the discovery of a new optical-IR synchrotron jet in the radio galaxy 3C133 from our HST/NICMOS snapshot survey. The jet and eastern hotspot are well resolved, and visible at both optical and IR wavelengths. The IR jet follows the morphology of the inner part of the radio jet, with three distinct knots identified with features in the radio. The radio-IR SED's of the knots are examined, along with those of two more distant hotspots at the eastern extreme of the radio feature. The detected emission appears to be synchrotron, with peaks in the NIR for all except one case, which exhibits a power-law spectrum throughout.Comment: ApJ accepted. 14 pages, 6 figure

Hidden in plain sight - Multiple resistant species within a strongyle community

Ovine parasitic gastroenteritis is a complex disease routinely treated using anthelmintics. Although many different strongyle species may contribute to parasitic gastroenteritis, not all are equally pathogenic: in temperate regions, the primary pathogen is Teladorsagia circumcincta. In this study we investigated benzimidazole and ivermectin resistance on a commercial sheep farm in southeast Scotland. We assessed the impact of species diversity on the diagnosis of resistance using the faecal egg count reduction test and in vitro bioassays, and correlated the results with the frequency of benzimidazole resistance-associated genotypes measured in the T. circumcincta population by pyrosequencing of the β-tubulin isotype-1 gene. Faecal egg count reduction test results showed efficacies of 65% for albendazole and 77% for ivermectin, indicating moderate resistance levels on the farm. However, PCR speciation of the same populations pre- and post-treatment revealed that removal of susceptible species had masked the presence of a highly resistant population of T. circumcincta. Less than 25% of individuals in the pre-treatment populations were T. circumcincta, the remainder consisting of Cooperia curticei, Chabertia ovina, Oesophagostomum venulosum and Trichostrongylus spp. In contrast, post-treatment with albendazole or ivermectin, the majority (88% and 100% respectively) of the populations consisted of T. circumcincta. The egg hatch test for benzimidazole resistance and the larval development test for ivermectin resistance were carried out using eggs obtained from the same populations and the results were broadly consistent with the faecal egg count reduction test. Thirty individual T. circumcincta from each sampling time point were assessed for benzimidazole resistance by pyrosequencing, revealing a high frequency and diversity of resistance-associated mutations, including within the population sampled post-ivermectin treatment. These results highlight the potential diversity of parasite species present on UK farms, and their importance in the diagnosis of anthelmintic resistance. On this particular farm, we demonstrate the presence of a highly dual-resistant population of T. circumcincta, which was strongly selected by treatment with either benzimidazoles or ivermectin, while other potentially less pathogenic species were removed

Increased expression of a microRNA correlates with anthelmintic resistance in parasitic nematodes

Resistance to anthelmintic drugs is a major problem in the global fight against parasitic nematodes infecting humans and animals. While previous studies have identified mutations in drug target genes in resistant parasites, changes in the expression levels of both targets and transporters have also been reported. The mechanisms underlying these changes in gene expression are unresolved. Here, we take a novel approach to this problem by investigating the role of small regulatory RNAs in drug resistant strains of the important parasite Haemonchus contortus. microRNAs (miRNAs) are small (22 nt) non-coding RNAs that regulate gene expression by binding predominantly to the 3′ UTR of mRNAs. Changes in miRNA expression have been implicated in drug resistance in a variety of tumor cells. In this study, we focused on two geographically distinct ivermectin resistant strains of H. contortus and two lines generated by multiple rounds of backcrossing between susceptible and resistant parents, with ivermectin selection. All four resistant strains showed significantly increased expression of a single miRNA, hco-miR-9551, compared to the susceptible strain. This same miRNA is also upregulated in a multi-drug-resistant strain of the related nematode Teladorsagia circumcincta. hco-miR-9551 is enriched in female worms, is likely to be located on the X chromosome and is restricted to clade V parasitic nematodes. Genes containing predicted binding sites for hco-miR-9551 were identified computationally and refined based on differential expression in a transcriptomic dataset prepared from the same drug resistant and susceptible strains. This analysis identified three putative target mRNAs, one of which, a CHAC domain containing protein, is located in a region of the H. contortus genome introgressed from the resistant parent. hco-miR-9551 was shown to interact with the 3′ UTR of this gene by dual luciferase assay. This study is the first to suggest a role for miRNAs and the genes they regulate in drug resistant parasitic nematodes. miR-9551 also has potential as a biomarker of resistance in different nematode species

The Reddest Quasars

In a survey of quasar candidates selected by matching the FIRST and 2MASS catalogs, we have found two extraordinarily red quasars. FIRST J013435.7-093102 is a 1 Jy source at z=2.216 and has B-K > 10, while FIRST J073820.1+275045 is a 2.5 mJy source at z=1.985 with B-K = 8.4. FIRST J073820.1+275045 has strong absorption lines of MgII and CIV in the rest frame of the quasar and is highly polarized in the rest frame ultraviolet, strongly favoring the interpretation that its red spectral energy distribution is caused by dust reddening local to the quasar. FIRST J073820.1+275045 is thus one of the few low radio-luminosity, highly dust-reddened quasars known. The available observational evidence for FIRST J013435.7-093102 leads us to conclude that it too is reddened by dust. We show that FIRST J013435.7-093102 is gravitationally lensed, increasing the number of known lensed, extremely dust-reddened quasars to at least three, including MG0414-0534 and PKS1830-211. We discuss the implications of whether these objects are reddened by dust in the host or lensing galaxies. If reddened by their local environment, then we estimate that between 10 and 20% of the radio-loud quasar population is reddened by dust in the host galaxy. The discovery of FIRST J073820.1+275045 and objects now emerging from X-ray surveys suggests the existence of an analogous radio-quiet red quasar population. Such objects will be entirely missed by standard radio or optical quasar surveys. If dust in the lensing galaxies is primarily responsible for the extreme redness of the lensed quasars, then an untold number of gravitationally lensed quasars are being overlooked.Comment: AASTEX 24 pp., 7 figs; accepted by ApJ. See also the preprint astro-ph/0107435 by Winn et al., who independently discovered that J013435.7-093102 is gravitationally lense

Validating the utilisation of venous bicarbonate as a predictor of acute kidney injury in crush syndrome from sjambok injuries

Background. Crush injury secondary to sjambok beatings is a well-described phenomenon in southern Africa. Owing to a number of factors, it can result in acute kidney injury (AKI). In 1992, Muckart et al. described a risk stratification system using venous bicarbonate (VB) that can be used in the management of these patients.Objective. To validate this score in the modern era of AKI risk stratification.Methods. A retrospective study was performed on a local trauma database from June 2010 to December 2012. All patients with crush injury from sjambok/blunt instrument beatings were included in the analysis. VB was compared with the Kidney Disease Improving Global Outcomes scoring system for AKI. Serum base excess (BE) and creatine kinase were also examined as biomarkers. The endpoints were the need for renal replacement therapy (RRT) and mortality.Results. Three hundred and ten patients were included. The overall mortality rate was 1.9%, 14.8% of patients had AKI, and 3.9% required RRT. Both VB and BE performed well in RRT prediction, with areas under the receiver operating characteristic curve of 0.847 (95% confidence interval (CI) 0.756 - 0.938; p&lt;0.001) and 0.871 (95% CI 0.795 - 0.947; p&lt;0.001), respectively. The sensitivity and specificity of BE were 83.3% and 80.2% at an optimal cut-point of –7.25 mmol/L, while those of VB were 83.3% and 79.5% at an optimal cut-point of 18.85 mmol/L. VB was significantly different across the AKI risk groups (p&lt;0.001), in keeping with the original Muckart risk stratification system.Conclusion. The risk stratification score using VB is valid and should continue to be used as a tool in the management of patients with sjambok injuries. BE performs well in predicting the need for RRT, with a value of &lt;–7.25 mmol/L indicating severe injury.