Antibiotic and insecticide resistance modeling--is it time to start talking?

Mathematical models have played an important part in understanding both antibiotic and insecticide resistance. However, there has been little, if any, interdisciplinary work between these two areas of active research. One primary reason for this is that bacterial population genetics differ substantially from the population genetics of diploid organisms. This article examines these differences and their effect on resistance. It explores what efforts have gone into modeling resistance mathematically in both arenas, and offers suggestions on how the two groups could work together to gain a more comprehensive understanding of the resistance phenomenon     

Baculovirus resistance in the noctuid Spodoptera exempta is phenotypically plastic and responds to population density

Parasite resistance mechanisms can be costly to maintain. We would therefore predict that organisms should invest in resistance only when it is likely to be required. Insects that show density-dependent phase polyphenism, developing different phenotypes at high and low population densities, have the opportunity to match their levels of investment in resistance with the likelihood of exposure to pathogens. As high population densities often precipitate disease epidemics, the high-density form should be selected to invest relatively more in resistance. We tested this prediction in larvae of the noctuid Spodoptera exempta. Larvae reared at a high density were found to be considerably more resistant to a nuclear polyhedrosis virus than those reared in isolation. A conspicuous feature of the high-density phase of S. exempta and other phase-polyphenic Lepidoptera is cuticular melanization. As melanization is controlled by the phenoloxidase enzyme system, which is also involved in the immune response, this suggests a possible mechanism for increased resistance at high population densities. We demonstrated that melanized S. exempta larvae were more resistant than non-melanized forms, independent of rearing density. We also found that haemolymph phenoloxidase activity was correlated with cuticular melanization, providing further evidence for a link between melanization and immunity. These results suggest that pathogen resistance in S. exempta is phenotypically plastic, and that the melanized cuticles characteristic of the high-density form may be indicative of a more active immune system.     

Bioassay for detecting active site insensitivity in horn fly (Diptera: Muscidae) larvae

A bioassay was used to detect active site insensitivity (knock-down resistance [kdr]) in pyrethroid resistant larvae of the horn fly, Haematobia irritans (L.). The larvae of the resistant population had KD50's 42.0-, 28.1- and 29.2-fold greater to permethrin, fenvalerate and lambda-cyhalothrin, respectively, compared with the susceptible population. In filter paper bioassays, resistant adult horn flies were 17 to 39.1 times less susceptible to the pyrethroids than susceptible adults at LC50. These results further document active site insensitivity as the major mechanism of pyrethroid resistance in the horn fly.     

Spider mite resistance to miticides in South Carolina strawberry and implications for improved integrated pest management

Tetranychus urticae Koch (Acari: Tetranychidae), twospotted spider mite, is a major secondary pest of strawberry and can cause significant yield loss. Tetranychus urticae is typically controlled using miticides, which has led to rapid resistance development. In South Carolina (USA), extension agents and growers have reported field failures of miticides (inadequate pest suppression), but resistance has not been quantitatively determined. In 2018, we determined the level of miticide resistance of six T. urticae populations found on strawberry across South Carolina. We examined efficacy of all miticides registered for use on US strawberry by conducting an initial diagnostic bioassay at 20% of the maximum labeled field rate. Any population?×?active ingredient combination resulting in?<?55% mortality was identified as ‘potentially resistant’ and concentration–response bioassays were then conducted to calculate LC₅₀ values for an individual population. These values were compared with those of a known-susceptible laboratory population to calculate resistance ratios (RR). Our results indicate that examined South Carolina populations of T. urticae from strawberry were highly resistant to bifenthrin (RR?=?100–60,000) and there was reduced susceptibility to fenbutatin-oxide (RR?=?25–123). The 'Sardinia' population had decreased abamectin susceptibility (RR?=?25). No resistance to hexythiazox, etoxazole, acequinocyl, bifenazate, fenpyroximate, spiromesifen, or cyflumetofen was found. Based on available data, it appears that miticide resistance is not a likely cause of field failures and issues related to application error and coverage should be investigated. Overall, this work supports the need to reduce the use of broad-spectrum pesticides and older products, in favor of newer miticide chemistries due to resistance issues.

     

Insulin resistance -- the role of ethnicity: evidence from Caucasian and African cohorts.

The risk for insulin resistance and subsequent type 2 diabetes varies between different ethnic populations due to differences in the genetic and environmental background. However, obesity and unhealthy lifestyle, crucial determinants of insulin resistance, are on the rise throughout all population groups though the susceptibility towards those factors may differ. Up to the present day it is not clear whether insulin resistance is based on metabolic changes due to lifestyle modifications or rather an ethnic and thus genetic grounded phenomenon. Genetic variations in secretion products of the active fat tissue (adipokines), a different pathophysiology of changes in glucose metabolism and the deep impact of urbanization (environmental factors) are discussed as primary determinants for differences in manifestation of insulin resistance between Caucasian and African populations. These factors may be influenced or modified by a central theme: visceral obesity. This mini review will elaborate on these issues illustrated by observations from Caucasian and African cohorts.     

Virulence of Meloidogyne spp. and Induced Resistance in Grape Rootstocks

Harmony grape rootstock displays resistance to several Meloidogyne spp. but that resistance is not durable in commercial vineyard settings. A 2-year experiment in a microplot setting revealed host specificities of two virulent populations of Meloidogyne arenaria and an avirulent population of Meloidogyne incognita. In a subsequent split-root experiment, the avirulent nematode population was demonstrated to induce resistance to the virulent nematode population. To quantify the level of resistance, reproduction of the virulent nematode population was determined 63 days after being challenged by an avirulent nematode population using a range of inoculum densities and timeframes. Induction of resistance became apparent when the virulent nematode population was inoculated 7 days after the avirulent nematode population and increased thereafter. The level of induced resistance increased with increased inoculum levels of the avirulent nematode population. Root systems of perennial crops are commonly fed upon simultaneously by multiple nematode species. These two studies indicate that field populations can become preferentially virulent upon one or multiple rootstocks and that co-inhabiting populations may induce existing resistance mechanisms. In perennial crops, it is common for numerous nematode species besides Meloidogyne spp. to be present, including some that feed without causing apparent damage.     

Comparative susceptibility studies of clinically isolated Pseudomonas aeruginosa, Escherichia coli and Klebsiella spp to cefoperazone and cefotaxime

The in-vitro activity of cefotaxime and cefoperazone were compared using clinically isolated Escherichia coli, Klebsiella spp and Pseudomonas aeruginosa. Cefotaxime was found on a weight to weight basis, to be much more active than cefoperazone. All the three species studied show the presence of cefoperazone-resistant population which were sensitive to cefotaxime. The possible mechanisms of resistance to these antibiotics were discussed.     

Transposon-mediated resistance to Bacillus sphaericus in a field-evolved population of Culex pipiens (Diptera: Culicidae)

The binary toxin is the major active component of Bacillus sphaericus, a microbial larvicide used for controlling some vector mosquito-borne diseases. B. sphaericus resistance has been reported in many part of the world, leading to a growing concern for the usefulness of this environmental friendly insecticide. Here we characterize a novel mechanism of resistance to the binary toxin in a natural population of the West Nile virus vector, Culex pipiens. We show that the insertion of a transposable element-like DNA into the coding sequence of the midgut toxin receptor induces a new mRNA splicing event, unmasking cryptic donor and acceptor sites located in the host gene. The creation of the new intron causes the expression of an altered membrane protein, which is incapable of interacting with the toxin, thus providing the host mosquito with an advantageous phenotype. As a large portion of insect genomes is composed of transposable elements or transposable elements-related sequences, this new mechanism may be of general importance to appreciate their significance as potent agents for insect resistance to the microbial insecticides.     

Dynamics and structure of developing wolf population under anthropogenic pressure: Features and patterns

The impact of hunting pressure on the main indices of wolf population in the phase of growth was studied. The resistance of the intrapopulation adaptations to anthropogenic impact is demonstrated. It is of importance that family territories become flexible in a developing population, which favors active formation of new families and spatial compression of wolf population. Analysis of the available field and published data indicates a two-stage pattern of the population growth phase and a synchronous transition of wolf populations to this phase.     

Acquisition of resistance genes by the IncQ plasmid R1162 is limited by its high copy number and lack of a partitioning mechanism.

R1162 is a representative member of the broad-host-range IncQ group of multicopy plasmids. Lower-copy-number derivatives of R1162 were constructed in vitro and shown to be unstable, indicating that partitioning of plasmid copies at cell division is due to random distribution and not to an active partitioning mechanism. However, the normal copy number of R1162 reduces cell fitness during growth in broth and favors the emergence of unstable, lower-copy-number variants. As a result, plasmid-borne antibiotic resistance genes active at a low copy number eventually result in plasmid loss during periods of no selection. We argue that the maintenance of R1162 in a population requires a gene that is selected only at high levels. This reduces the potential for acquiring genes from other R factors and could explain the limited variety of antibiotic resistance genes contained by naturally occurring IncQ plasmids.     

An anchored AFLP- and retrotransposon-based map of diploid Avena.

A saturated genetic map of diploid oat was constructed based on a recombinant inbred (RI) population developed from a cross between Avena strigosa (Cereal Introduction, C.I. 3815) and A. wiestii (C.I. 1994). This 513-locus map includes 372 AFLP (amplified fragment length polymorphism) and 78 S-SAP (sequence-specific-amplification polymorphism) markers, 6 crown-rust resistance loci, 8 resistance-gene analogs (RGAs), one morphological marker, one RAPD (random amplified polymorphic DNA) marker, and is anchored by 45 grass-genome RFLP (restriction fragment length polymorphism) markers. This new A. strigosa x A. wiestii RI map is colinear with a diploid Avena map from an A. atlantica x A. hirtula F2 population. However, some linkage blocks were rearranged as compared to the RFLP map derived from the progenitor A. strigosa x A. wiestii F2 population. Mapping of Bare-1-like sequences via sequence-specific AFLP indicated that related retrotransposons had considerable heterogeneity and widespread distribution in the diploid Avena genome. Novel amplified fragments detected in the RI population suggested that some of these retrotransposon-like sequences are active in diploid Avena. Three markers closely linked to the Pca crown-rust resistance cluster were identified via AFLP-based bulk-segregant analysis. The derived STS (sequence-tagged-site) marker, Agx4, cosegregates with Pc85, the gene that provides resistance specificity to crown-rust isolate 202 at the end of the cluster. This framework map will be useful in gene cloning, genetic mapping of qualitative genes, and positioning QTL (quantitative trait loci) of agricultural importance.     

HIV-1 protease molecular dynamics of a wild-type and of the V82F/I84V mutant: possible contributions to drug resistance and a potential new target site for drugs

The protease from type 1 human immunodeficiency virus (HIV-1) is a critical drug target against which many therapeutically useful inhibitors have been developed; however, the set of viral strains in the population has been shifting to become more drug-resistant. Because indirect effects are contributing to drug resistance, an examination of the dynamic structures of a wild-type and a mutant could be insightful. Consequently, this study examined structural properties sampled during 22 nsec, all atom molecular dynamics (MD) simulations (in explicit water) of both a wild-type and the drug-resistant V82F/I84V mutant of HIV-1 protease. The V82F/I84V mutation significantly decreases the binding affinity of all HIV-1 protease inhibitors currently used clinically. Simulations have shown that the curling of the tips of the active site flaps immediately results in flap opening. In the 22-nsec MD simulations presented here, more frequent and more rapid curling of the mutant's active site flap tips was observed. The mutant protease's flaps also opened farther than the wild-type's flaps did and displayed more flexibility. This suggests that the effect of the mutations on the equilibrium between the semiopen and closed conformations could be one aspect of the mechanism of drug resistance for this mutant. In addition, correlated fluctuations in the active site and periphery were noted that point to a possible binding site for allosteric inhibitors.     

High-Level Field Resistance to Bacillus sphaericus C3-41 in Culex quinquefasciatus from Southern China

A flowable mosquito-larvicidal formulation of Bacillus sphaericus strain C3-41 has been continuously used for 8 years to control Culex quinquefasciatus larvae in Dongguan, Guangdong Province, China. This formulation had high efficacy against the target larvae during the first 6 years of treatment. However, under this high selection pressure, C. quinquefasciatus showed a significant level of resistance to C3-41 from years seven to eight. The resistance ratio of field-collected larvae at LC 50 was calculated to be 22 672-fold in comparison with the susceptible laboratory colony. Interestingly, no cross-resistance was observed to B. sphaericus strain LP1-G which had the same toxicity against both susceptible and resistant larvae, and B. thuringiensis subsp. israelensis was found to be more active to the latter than the former. After six months treatment with the B. thuringiensis subsp. israelensis formulation in the B. sphaericus resistant population area, the mosquito population recovered its susceptibility to B. sphaericus C3-41, with the resistance ratio of field-collected larvae dropping from 22 672- to 5.67-fold.     

Deployment of disease resistance genes by plant transformation - a 'mix and match' approach

Breeding for disease resistance has often resulted in the evolution of a matching virulence within the pathogen population, leading to an apparent 'breakdown' of resistance. In general, plant breeders have responded by introducing new genes for resistance, with similar consequences. This has led to 'boom-bust' cycles, where varieties possessing effective resistance are grown on an expanding acreage (boom) until matching virulence evolves and spreads within the pathogen population (bust). A variety of resistance genes have recently been identified and characterized in model systems. Together with the development of efficient plant transformation systems these genes offer an alternative means to introduce specific resistance into a crop improvement programme. However, unless the resistance genes are deployed with care, the boom-bust cycle is likely to be perpetuated.     

A new amino-acid substitution in acetylcholinesterase 1 confers insecticide resistance to Culex pipiens mosquitoes from Cyprus

In insects, selection of insecticide-insensitive acetylcholinesterase (AChE) is a very common resistance mechanism. Mosquitoes possess both AChE1 and AChE2 enzymes and insensitivity is conferred by single amino-acid changes located near the active site of the synaptic AChE1. Only two positions have been reported so far to be involved in resistance, suggesting a very high structural constraint of the AChE1 enzyme. In particular, the G119S substitution was selected in several mosquitoes' species and is now largely spread worldwide. Yet, a different type of AChE1 insensitivity was described 10 years ago in a Culex pipiens population collected in Cyprus in 1987 and fixed thereafter as the ACE-R strain. We report here the complete amino-acid sequence of the ACE-R AChE1 and show that resistance is associated with a single Phe-to-Val substitution of residue 290, which also lines the active site. Comparison of AChE1 activities of the recombinant F290V protein and ACE-R mosquito extracts confirmed the causal role of the substitution in insensitivity. Biochemical characteristics of the mutated protein indicated that the resistance level varies with the insecticide used. A molecular diagnosis test was designed to detect this mutation and was used to show that it is still present in Cyprus Island.     

Virus epidemics can lead to a population‐wide spread of intragenomic parasites in a previously parasite‐free asexual population

Sexual reproduction is problematic to explain due to its costs, most notably the twofold cost of sex. Yet, sex has been suggested to be favourable in the presence of proliferating intragenomic parasites given that sexual recombination provides a mechanism to confine the accumulation of deleterious mutations. Kraaijeveld et al. compared recently the accumulation of transposons in sexually and asexually reproducing lines of the same species, the parasitoid wasp Leptopilina clavipes. They discovered that within asexually reproducing wasps, the number of gypsy‐like retrotransposons was increased fourfold, whereas other retrotransposons were not. Interestingly, gypsy‐like retrotransposons are closely related to retroviruses. Endogenous retroviruses are retroviruses that have integrated to the germ line cells and are inherited thereafter vertically. They can also replicate within the genome similarly to retrotransposons as well as form virus particles and infect previously uninfected cells. This highlights the possibility that endogenous retroviruses could play a role in the evolution of sexual reproduction. Here, we show with an individual‐based computational model that a virus epidemic within a previously parasite‐free asexual population may establish a new intragenomic parasite to the population. Moreover and in contrast to other transposons, the possibility of endogenous viruses to maintain a virus epidemic and simultaneously provide resistance to individuals carrying active endogenous viruses selects for the presence of active intragenomic parasites in the population despite their deleterious effects. Our results suggest that the viral nature of certain intragenomic parasites should be taken into account when sex and its benefits are being considered.     

Lactuca saligna,a non-host for lettuce downy mildew ( Bremia lactucae), harbors a new race-specific Dm gene and three QTLs for resistance

Lactuca sativa (lettuce) is susceptible to Bremia lactucae (downy mildew). In cultivated and wild Lactuca species, Dm genes have been identified that confer race-specific resistance. However, these genes were soon rendered ineffective by adaptation of the pathogen. Lactuca saligna (wild lettuce) is resistant to all downy mildew races and can be considered as a non-host. Therefore, L. saligna might be an alternative source for a more-durable resistance to downy mildew in lettuce. In order to analyze this resistance, we have developed an F(2) population based on a resistant L. saligna x susceptible L. sativa cross. This F(2) population was fingerprinted with AFLP markers and tested for resistance to two Bremia races NL14 and NL16. The F(2) population showed a wide and continuous range of resistance levels from completely resistant to completely susceptible. By comparison of disease tests, we observed a quantitative resistance against both Bremia races as well as a race-specific resistance to Bremia race NL16 and not to NL14. QTL mapping revealed a qualitative gene ( R39) involved in the race-specific resistance and three QTLs ( RBQ1, RBQ2 and RBQ3) involved in the quantitative resistance. The qualitative gene R39 is a dominant gene that gives nearly complete resistance to race NL16 in L. saligna CGN 5271 and therefore it showed features similar to Dm genes. The three QTLs explained 51% of the quantitative resistance against NL14, which indicated that probably only the major QTLs have been detected in this F(2) population. The perspectives for breeding for durable resistance are discussed.     

Functional and morphological characteristics of coronary vessels in varying degree of coronary perfusion]

Limitation of coronary perfusion of different degree induces inhomogeneous changes in resistance of vessels in the hypoperfusing zone: an adequate dilatory regulatory reaction may be followed by an increase in resistance of the coronary vessels. An active component of diastolic coronary resistance used to analyze vascular reactions, rate and character of changes in resistance under conditions of coronary perfusion as well as histological and electron-microscopic estimation of the vascular wall state testify to reversibility and active character of the observed changes in coronary resistance including its increase. This increase is pathogenetically significant as it may induce further development of the coronary perfusion disorder.     

抗杀螟硫磷二化螟的抗性遗传力研究

应用数量遗传学的方法分析了水稻二化螟(chilo suppressalis)对杀螟硫磷抗药性的遗传力,并就遗传力和杀虫剂的杀死率对抗性发展速率的影响进行了预测。研究结果表明：二化螟对杀螟硫磷抗性的遗传力较低(h²＝0.277),产生高抗性的潜力不大。即使在室内选择的条件下,要获得10倍的抗性约需要6-12代;在野外条件下则需要更长的时间(15-32代)。因此,结合抗性变化动态的监测结果,我们认为在野外条件下二化螟是不致于产生高抗性,杀螟硫磷仍不失为二化螟抗性治理系统中有效品种之一。