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Anticoagulant compounds, i.e., derivatives of either 4-hydroxycoumarin (e.g., warfarin, bromadiolone) or indane-1,3-dione (e.g., diphacinone, chlorophacinone), have been in worldwide use as rodenticides for >50 years. These compounds inhibit blood coagulation by repression of the vitamin K reductase reaction (VKOR). Anticoagulant-resistant rodent populations have been reported from many countries and pose a considerable problem for pest control. Resistance is transmitted as an autosomal dominant trait although, until recently, the basic genetic mutation was unknown. Here, we report on the identification of eight different mutations in the VKORC1 gene in resistant laboratory strains of brown rats and house mice and in wild-caught brown rats from various locations in Europe with five of these mutations affecting only two amino acids (Tyr139Cys, Tyr139Ser, Tyr139Phe and Leu128Gln, Leu128Ser). By recombinant expression of VKORC1 constructs in HEK293 cells we demonstrate that mutations at Tyr139 confer resistance to warfarin at variable degrees while the other mutations, in addition, dramatically reduce VKOR activity. Our data strongly argue for at least seven independent mutation events in brown rats and two in mice. They suggest that mutations in VKORC1 are the genetic basis of anticoagulant resistance in wild populations of rodents, although the mutations alone do not explain all aspects of resistance that have been reported. We hypothesize that these mutations, apart from generating structural changes in the VKORC1 protein, may induce compensatory mechanisms to maintain blood clotting. Our findings provide the basis for a DNA-based field monitoring of anticoagulant resistance in rodents.

The Daubenton's bat is widespread and common in the UK and countries bordering the English Channel and North Sea. European bat lyssavirus 2 (EBLV-2), a rabies virus, has been detected in Daubenton's bats in the UK and continental Europe. Investigating the relatedness of colonies and gene flow between these regions would allow regional estimates of the movement of Daubenton's bats and thus the potential for disease transmission. The genetic structure of the Daubenton's bat in western Europe was investigated by analysing variability at eight microsatellite loci. Genetic diversity was found to be high at all sites (H E = 0.73-0.84), with little differentiation between bats sampled in the UK and continental Europe. Mantel tests indicated a significant correlation between geographic distance and pair-wise F ST (P = 0.000), between colonies sampled in Scotland and northern England. However, this was not continuous throughout the sampled range, with evidence of panmixia within the area sampled in continental Europe. Assignment tests show no evidence that the (potential) EBLV-2 sero-positive and virus positive bats were more likely to have originated from the continental rather than UK populations. There is no sufficient significant genetic differentiation amongst most UK and continental colonies to conclude that EBLV-2 is maintained in the UK by immigration. Results show that it is likely to be maintained at a low endemic level within the UK. The relative genetic uniformity of UK and continental populations implies that there is no migration barrier to EBLV-2, between these regions.

The present study investigated the whole‐carcass residue carried by resistant and susceptible laboratory rat strains following 5, 10, or 20 d of feeding on a diet of 25 mg difenacoum/kg bait. The mean whole‐carcass residue of difenacoum was determined by high‐performance liquid chromatography to be between 0.52 and 0.74 mg/kg body weight in all three rat strains tested. These values were considerably lower than some comparable data previously reported for other species and second‐generation rodenticides as well as from mathematical models. The whole‐carcass residue of extractable (i.e., nonrefractory) parent compound carried by highly resistant rats fed for 20 d (0.74 mg/kg body wt) is unlikely to present a significantly increased risk to predators compared to the amount carried by susceptible rats after 5 d of feeding (0.52 mg/kg body wt). However, resistant rats are more likely to be available for predation and to be carrying a whole‐carcass residue of anticoagulant throughout the duration of a control program.

A modified Lorentzian distribution function is used to model peaks in two-dimensional (2D) ¹H-¹³C heteronuclear single quantum coherence (HSQC) nuclear magnetic resonance (NMR) spectra. The model fit is used to determine accurate chemical shifts from genuine signals in complex metabolite mixtures such as blood. The algorithm can be used to extract features from a set of spectra from different samples for exploratory metabolomics. First a reference spectrum is created in which the peak intensities are given by the median value over all samples at each point in the 2D spectra so that ¹H-¹³C correlations in any spectra are accounted for. The mathematical model provides a footprint for each peak in the reference spectrum, which can be used to bin the ¹H-¹³C correlations in each HSQC spectrum. The binned intensities are then used as variables in multivariate analyses and those found to be discriminatory are rapidly identified by cross referencing the chemical shifts of the bins with a database of ¹³C and ¹H chemical shift correlations from known metabolites.

Bromadiolone resistance in Norway rats (Rattus norvegicus) may reduce the efficacy of rodent control measures, and managers need a validated test to detect potential control problems. We developed a test to identify levels of resistance to the rodenticide bromadiolone in warfarin-resistant Norway rats. This test was based on changes in blood-clotting activity 4 days after administering a single dose of bromadiolone in conjunction with menadione sodium bisulphite (vitamin K3). The test procedure identified the degree of bromadiolone resistance in laboratory and wild note that had anticoagulant resistance genes. In addition, results were available within 5 days, and susceptible animal could be humanely culled rather than dying of anticoagulant poisoning, as occurs with feeding tests. The test was based on an effective dose needed for 99% response ($\\text{ED}_{99}$) for rats susceptible to all anticoagulants and results were determined separately for each sex. We report bromadiolone resistance in Norway rats for the first time in the United Kingdom and that rats in central southern England have a higher degree of resistance than do rats from Wales or Yorkshire.

A modified Lorentzian distribution function is used to model peaks in two-dimensional (2D) ^sup 1^H-^sup 13^C heteronuclear single quantum coherence (HSQC) nuclear magnetic resonance (NMR) spectra. The model fit is used to determine accurate chemical shifts from genuine signals in complex metabolite mixtures such as blood. The algorithm can be used to extract features from a set of spectra from different samples for exploratory metabolomics. First a reference spectrum is created in which the peak intensities are given by the median value over all samples at each point in the 2D spectra so that ^sup 1^H-^sup 13^C correlations in any spectra are accounted for. The mathematical model provides a footprint for each peak in the reference spectrum, which can be used to bin the ^sup 1^H-^sup 13^C correlations in each HSQC spectrum. The binned intensities are then used as variables in multivariate analyses and those found to be discriminatory are rapidly identified by cross referencing the chemical shifts of the bins with a database of ^sup 13^C and ^sup 1^H chemical shift correlations from known metabolites.

We conducted a study to ascertain if an observed reduction of susceptibility to brodifacoum in Norway rats (Rattus norvegicus) present on at least 3 farms in Berkshire, United Kingdom, was heritable. This trait was demonstrated in individual rats by their survival after consumption of 0.0005% (m/m) brodifacoum in the diet for 7 days (Gill and MacNicoll 1991) and is termed \"low grade\" resistance. It is inherited through at least 5 generations and is not associated with vitamin K deficiency. Our data also suggest a different explanation for the inheritance of difenacoum resistance compared with that reported by Greaves and Cullen-Ayres (1988). We suggest that difenacoum resistance in these animals arises from an autosomal dominant anticoagulant resistance gene with a recessive sex-linked modifier. Brodifacoum resistance also is due to the same major gene with recessive sex linked modifiers, but with additional modifiers present that may or may not be sex-linked. The Berkshire anticoagulant resistance gene appears to be different from the Hampshire gene previously reported by Greaves and Cullen-Ayres (1988), because no vitamin K deficiency occurs after feeding for 4 days on vitamin K-free diet. Although these rats survived higher doses of brodifacoum than susceptible individuals in the laboratory, the practical results of this resistance on the outcome of field control treatments are unknown.