The emergence of resistance to the benzimidazole anthlemintics in parasitic nematodes of livestock is characterised by multiple independent hard and soft selective sweeps

Anthelmintic resistance is a major problem for the control of parasitic nematodes of livestock and of growing concern for human parasite control. However, there is little understanding of how resistance arises and spreads or of the “genetic signature” of selection for this group of important pathogens. We have investigated these questions in the system for which anthelmintic resistance is most advanced; benzimidazole resistance in the sheep parasites Haemonchus contortus and Teladorsagia circumcincta. Population genetic analysis with neutral microsatellite markers reveals that T. circumcincta has higher genetic diversity but lower genetic differentiation between farms than H. contortus in the UK. We propose that this is due to epidemiological differences between the two parasites resulting in greater seasonal bottlenecking of H. contortus. There is a remarkably high level of resistance haplotype diversity in both parasites compared with drug resistance studies in other eukaryotic systems. Our analysis suggests a minimum of four independent origins of resistance mutations on just seven farms for H. contortus, and even more for T. circumincta. Both hard and soft selective sweeps have occurred with striking differences between individual farms. The sweeps are generally softer for T. circumcincta than H. contortus, consistent with its higher level of genetic diversity and consequent greater availability of new mutations. We propose a model in which multiple independent resistance mutations recurrently arise and spread by migration to explain the widespread occurrence of resistance in these parasites. Finally, in spite of the complex haplotypic diversity, we show that selection can be detected at the target locus using simple measures of genetic diversity and departures from neutrality. This work has important implications for the application of genome-wide approaches to identify new anthelmintic resistance loci and the likelihood of anthelmintic resistance emerging as selection pressure is increased in human soil-transmitted nematodes by community wide treatment programs

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

Evaluation of REE mobility in low-grade metabasalts using mass-balance calculations

Some studies of rare-earth element (REE) pattems of altered basalts have suggested that REE may be mobile during alteration. When possible effects of total rock mass balance are considered, most published data suggest that (l) only La is required to have been mobile, (2) if other REE have been mobile, changes are within analytical error and do not correlate with mineralogical or major-element changes during alteration, and (3) at !east some other 'immobile' elements, such as Ti, Y, and Zr, may have been mobile in the rocks considered here. REE, excluding La, may be among the most reliable geochemical indicators of the compositional affinities of altered basalts

Structural geology, metamorphism, and Rb/Sr geochronology of East Hinnøy, North Norway

Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Earth and Planetary Sciences, 1981.Microfiche copy available in Archives and Science.Accompanied by 7 folded plates inserted in back pocket.Bibliography: leaves 256-263.by John Michael Bartley.Ph.D

Personality matters : exploring the relationship between personality and stress physiology in captive African lions

Background: Considering animals as individuals and not as species is becoming increasingly essential to animal welfare management in captive settings. Recent studies on big cat personalities and coping strategies suggest personality can help big cats cope in their surroundings. Yet a large portion of the published literature focuses on understanding either the personality or stress physiology of big cats. Our research shows how integrating an improved understanding of the personality of big cats with stress physiology may enhance welfare, especially for endangered species like African lions. By using a wild cat personality checklist, this study compared the key personality dimensions of 22 African lions with its faecal glucocorticoids and assessed factors influencing their personality and stress physiology. Results: We found two reliable personality dimensions for African lions (dominance and agreeableness) and identified key factors (sex, age and location) that may influence their personality. Further, on testing if these factors influenced the stress physiology through variations in glucocorticoid levels, there was no significant difference. However, there was a strong negative association between agreeableness and glucocorticoid levels. These results suggest that the behavioural traits loading positively and higher for agreeableness are associated with lower glucocorticoid stress levels, which may assist a lion to cope with stressors in its surroundings. Conclusions: Our findings highlight this integrated approach of linking personality and stress physiology of big cats can be beneficial for caretakers. For example, during stressful veterinary procedures or in reintroduction programs, recognizing the personality of lions can help in designing or providing them with resources that will alleviate stress. Thus, there is a need for more interdisciplinary approaches that will contribute towards enhancing the individual and overall welfare of big cats

In vivo and in vitro metabolism of 4-benzo(b)thienyl-N-methylcarbamate and 4-hydroxy benzothiophene by the white rat

In vitro studies of Mobam (4-benzo(b)thienyl N-methylcarbamate) metabolism have demonstrated that at least three ether soluble metabolites are formed in a microsomal system fortified with reduced triphosphopyridine nucleotide (NADPH). One of the metabolites was identical to 4HBT (4-hydroxy benzothiophene), the phenol of Mobam. The other two metabolites did not possess the carbonyl carbon of Mobam and therefore involved hydrolysis of the ester linkage. Water soluble metabolites of Mobam and 4HBT were produced by NADPH-dependent microsomal reactions. One of the metabolites contained the carbonyl carbon of Mobam but not the ring moiety. The added cofactors UDPGA (uridine diphosphoglucuronic acid) and ATP/SO₄[subscript =]/Mg⁺⁺ resulted in the formation of specific metabolites of the ring moiety. One of these products is tentatively identified as the glucuronide of 4HBT. No reaction between the carbamic acid portion of the carbamate and UDPGA was observed. In vivo metabolism of Mobam or 4HBT led to the rapid excretion or expiration of the metabolic products. Approximately 80% of the ring moiety and more than 40% of the carbonyl carbon were excreted in the urine within 72 hours after treatment of the rat. An additional one-fourth of the carbonyl carbon was expired as carbon dioxide indicating hydrolysis of the ester linkage and splitting of the C-N bond of the carbamic acid. Besides expired carbon dioxide, four other in vivo metabolites were characterized by their paper chromatographic Rf values. One of these metabolites arose from the carbamic acid moiety and the other three contained the ring structure but not the carbonyl carbon. One of the ring metabolites is tentatively identified as the glucuronide of 4HBT and another may be the sulfate conjugate of 4HBT. Each of the major metabolites of Mobam was also excreted by rats treated with 4HBT, demonstrating the close relationship between the metabolic fate of Mobam and its phenol

In vivo and in vitro metabolism of 4-benzo(b)thienyl-N-methylcarbamate and 4-hydroxy benzothiophene by the white rat

In vitro studies of Mobam (4-benzo(b)thienyl N-methylcarbamate) metabolism have demonstrated that at least three ether soluble metabolites are formed in a microsomal system fortified with reduced triphosphopyridine nucleotide (NADPH). One of the metabolites was identical to 4HBT (4-hydroxy benzothiophene), the phenol of Mobam. The other two metabolites did not possess the carbonyl carbon of Mobam and therefore involved hydrolysis of the ester linkage. Water soluble metabolites of Mobam and 4HBT were produced by NADPH-dependent microsomal reactions. One of the metabolites contained the carbonyl carbon of Mobam but not the ring moiety. The added cofactors UDPGA (uridine diphosphoglucuronic acid) and ATP/SO₄[subscript =]/Mg⁺⁺ resulted in the formation of specific metabolites of the ring moiety. One of these products is tentatively identified as the glucuronide of 4HBT. No reaction between the carbamic acid portion of the carbamate and UDPGA was observed. In vivo metabolism of Mobam or 4HBT led to the rapid excretion or expiration of the metabolic products. Approximately 80% of the ring moiety and more than 40% of the carbonyl carbon were excreted in the urine within 72 hours after treatment of the rat. An additional one-fourth of the carbonyl carbon was expired as carbon dioxide indicating hydrolysis of the ester linkage and splitting of the C-N bond of the carbamic acid. Besides expired carbon dioxide, four other in vivo metabolites were characterized by their paper chromatographic Rf values. One of these metabolites arose from the carbamic acid moiety and the other three contained the ring structure but not the carbonyl carbon. One of the ring metabolites is tentatively identified as the glucuronide of 4HBT and another may be the sulfate conjugate of 4HBT. Each of the major metabolites of Mobam was also excreted by rats treated with 4HBT, demonstrating the close relationship between the metabolic fate of Mobam and its phenol

Clinical trial of FK 506 immunosuppression in adult cardiac transplantation

The new immunosuppressive agent FK 506 was used as primary immunotherapy in conjunction with low-dose steroids and azathioprine in 72 patients subsequent to orthotopic cardiac transplantation. Overall patient survival at a mean follow-up of 360 days was 92%. The number of episodes of cardiac rejection (grade 3A or greater) within 90 days of transplantation was 0.95 per patient. The actuarial freedom from rejection at 90 days was 41%. Achievement of this level of immunosuppression is comparable with that of cyclosporine-based triple-drug therapy with OKT3 immunoprophylaxis. Thirty percent of patients were tapered off all steroids, and the average steroid dose in the group who received steroids was 8.6 mg of prednisone per day. The incidence of infection reflected the diminished necessity for steroids: seven major infections (10%) and 11 minor infections (16%). Renal dysfunction occurred during the perioperative period in most patients in this trial. However, the incidence of hypertension was 54% compared with 70% during the cyclosporine era. Ten adults underwent successful rescue therapy with FK 506 after cardiac rejection refractory to conventional immunotherapy. Side effects of FK 506 were notably few, and the results of the trial are encouraging for the future of the cardiac transplant recipient. © 1992

Timing of Tertiary Extension in the Railroad Valley Pioche Transect, Nevada: Constraints from Ar-40/Ar-39 Ages of Volcanic Rocks

Time-space relations of extension and volcanism place critical constraints on models of Basin and Range extensional processes. This paper addresses such relations in a 130-km-wide transect in the eastern Great Basin, bounded on the east by the Ely Springs Range and on the west by the Grant and Quinn Canyon ranges. Stratigraphic and structural data, combined with 40Ar/39Ar isotopic ages of volcanic rocks, document a protracted but distinctly episodic extensional history. Field relations indicate four periods of faulting. Only one of these periods was synchronous with nearby volcanic activity, which implies that volcanism and faulting need not be associated closely in space and time. Based on published dates and the analyses reported here, the periods of extension were (1) prevolcanic (pre-32 Ma), (2) early synvolcanic (30 to 27 Ma), (3) immediately postvolcanic (about 16 to 14 Ma), and (4) Pliocene to Quaternary. The break between the second and third periods is distinct. The minimum gap between the first two periods is 2 Ma, but the separation may be much larger. Temporal separation of the last two periods is only suggested by the stratigraphic record and cannot be rigorously demonstrated with present data. The three younger periods of faulting apparently occurred across the entire transect. The oldest period is recognized only at the eastern end of the transect, but appears to correlate about 150 km northward along strike with extension in the Northern Snake Range-Kern Mountains area. Therefore the oldest period also is regional in extent, but affected a different area than that affected by younger periods. This relation suggests that distinct extensional structures and master detachment faults were active at different times. The correlation of deformation periods of a few million years duration across the Railroad Valley-Pioche transect suggests that the scale of active extensional domains in the Great Basin may be greater than 100 km across strike