Pyrethroid insecticides alter the normal gating of voltage-gated sodium channels in the nervous system. Three sodium channel mutations (E434K, C764R, L993F) were recently identified in pyrethroid resistant German cockroach populations. In this report, we show that the L993F mutation decreased sodium channel sensitivity to the pyrethroid, deltamethrin, by five-fold in Xenopus oocytes. In contrast, neither E434K nor C764R alone decreased channel sensitivity to deltamethrin. However, E434K or C764R combined with L993F reduced deltamethrin sensitivity by 100-fold. Furthermore, concomitant presence of all three mutations (KRF) reduced channel sensitivity to deltamethrin by 500-fold. None of the mutations significantly affected channel gating. However, sodium current amplitudes from the mutant sodium channel carrying either E434K or C764R alone were much reduced compared to those of the wild-type channel or the channel carrying the double or triple mutations (KF, RF and KRF). These results indicated that evolution of sodium channel insensitivity in the German cockroach is achieved by sequential selection of a primary mutation L993F and two secondary mutations E434K and C764R, and concomitant presence of all three mutations dramatically reduced sodium channel sensitivity to deltamethrin.

The traditional linear envelope model is widely used in linac design and on-line tuning. However, for the simultaneous acceleration of multicharge states, the associated transfer matrix acts differently on each species with different charge to mass ratios and the traditional linear envelope model cannot be utilized. A direct way to handle multicharge state acceleration is by using multiparticle tracking, which can be high in model detail, but is typically lacking in computational efficiency to the extent where it is not suitable for on-line beam tuning of a linac. In this paper, a new approach of adapting a conventional linear envelope model to multicharge state acceleration is developed. The lattice of the proposed Facility for Rare Isotope Beams (FRIB) is used to test this technique in both the linac and the bend/folding segments of the machine. Results are benchmarked with the multiparticle tracking code IMPACT to both verify the accuracy of the model and clarify improvements in computational efficiency.

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