Stochastic optimal therapy for enhanced immune response

Therapeutic enhancement of humoral immune response to microbial attack is addressed as the stochastic optimal control of a dynamic system. Without therapy, the modeled immune response depends upon the initial concentration of pathogens in a simulated attack. Immune response can be augmented by agents that kill the pathogen directly, that stimulate the production of plasma cells or antibodies, or that enhance organ health. Using a generic mathematical model of immune response to the infection (i.e., of the dynamic state of the system), previous papers demonstrated optimal (open-loop) and neighboring-optimal (closed-loop) control solutions that defeat the pathogen and preserve organ health, given initial conditions that otherwise would be lethal [Optimal Contr. Appl. Methods 23 (2002) 91, Bioinformatics 18 (2002) 1227]. Therapies based on separate and combined application of the agents were derived by minimizing a quadratic cost function that weighted both system response and drug usage, providing implicit control over harmful side effects. Here, we focus on the effects that corrupted or incomplete measurements of the dynamic state may have on neighboring-optimal feedback control. Imperfect measurements degrade the precision of feedback adjustments to therapy; however, optimal state estimation allows the feedback strategy to be implemented with incomplete measurements and minimizes the expected effects of measurement error. Complete observability of the perturbed state for this four state example is provided by measurement of four of the six possible pairs of two variables, either set of three variables, or all four variables. The inclusion of state estimation extends the applicability of optimal control theory for developing new therapeutic protocols to enhance immune response.     

Contrasting evolutionary forces driving population structure at expressed sequence tag polymorphisms, allozymes and quantitative traits in white spruce

Patterns of variation in quantitative characters and genetic markers were compared among six regional populations of white spruce [Picea glauca (Moench) Voss]. Although some phenotypic characters were correlated with latitude (r = 0.791), longitude (r = -0.796) and precipitation during the growing season (r = 0.789), variability at genetic markers was not correlated with geographical or bioclimatic variables, and followed neutral expectations. Estimates of genetic diversity and population differentiation for 14 allozymes (translated regions of coding genes) were essentially indistinguishable from those observed for 11 expressed sequence tag polymorphisms (ESTPs) from untranslated regions of coding genes. Variation among populations for quantitative traits such as eighth year height (Q(ST) = 0.082), thirteenth year height (Q(ST) = 0.069), total wood density (Q(ST) = 0.102) and date of budset (Q(ST) = 0.246), was greater than for allozymes (G(ST) = 0.014) and ESTPs (G(ST) = 0.019). These trends suggest a strong adaptive response in quantitative traits, contrasting to allozymes and ESTPs where no selective response could be detected and where populations appeared to be essentially in a migration-drift equilibrium.     

Genetic variability in two West Indian anoles (Reptilia, Iguanidae): relation to field thermal biology

Meristic and electrophoretic characters were used as independent estimators of genetic variability within populations of two West Indian Anolis lizard species. The species which uses flexible regulatory behaviours to maintain thermal homeostasis, A. roquet on Martinique, exhibited much less within-population electrophoretic variability than did the species which is behaviourally passive to changes in the thermal environment, A. gundlachi on Puerto Rico. The data suggest that the high genetic variability in A. gundlachi may be an adaptation to its coarse-grained perception of seasonal variation in the thermal environment, whereas A. roquet's low genetic variability may be adaptive because its flexible regulatory behaviours provide a temporally fine-grained perception of the thermal environment. Meristic characters did not demonstrate any interspecific difference in the amount of within-population genetic variability. Discordance in the results of the meristic and electrophoretic analyses suggest either that the two character sets sample dramatically different genetic phenomena or that environmental effects on the development of meristic characters render them unreliable as indicators of the genetic variability within geographically proximate populations.     

SEX RATIO VARIATION IN A PARASITIC WASP I. REACTION NORMS

To understand genetic and phenotypic constraints on the sex ratio in a parasitic wasp that attacks fly pupae, I carried out a laboratory study of sex ratio variability in five strains of Muscidifurax raptor (Hymenoptera: Pteromalidae). I manipulated the environment through combinations of temperature and day length, and the numbers of females that attack a group of hosts. The change of phenotype in each strain over the range of environmental conditions describes the norm of each reaction for that strain, and measures how a strain responds to environmental variation to create phenotypic variability. Sex ratio in parasitic wasps is a complex trait that has several components—the numbers of eggs laid by an ovipositing wasp and the fraction of eggs that are fertilized (female). Further, sex ratio may be influenced by a female's reaction to other females exploiting the same hosts (superparasitism). I found no strain-environment interactions in either sex ratio or fecundity when I varied environmental conditions. Although strains differed in sex ratio and fecundity, all strains produced a more female-biased sex ratio and had higher fecundity when temperature and day length increased. Sex ratio and fecundity were phenotypically correlated, and strains with greater fecundity also produced a more female-biased sex ratio. All strains facultatively shifted sex ratio toward a higher fraction of males with increasing female density, despite apparent differences in superparasitism among strains. Males and females survived equally during development, so that mortality differences among strains and across environments could not account for sex ratio variability. This study indicates that sex ratio variability among strains is constrained by the correlation between sex ratio and fecundity, and that strains display similar facultative shifts in sex ratio as female density increases because sex ratio shifts are insensitive to differing levels of superparasitism.     

The use of antisense oligonucleotides as chemotherapeutic agents for parasites

Although several approaches to the control of human parasites are possible, the prevention and therapy of the corresponding diseases still remain a difficult task. The development of vaccines has been hampered by the poor immunological response to or the high variability of parasitic antigens. Problems also arise for chemotherapy where differences in the biochemistry of host and parasite must be exploited. The increasingly difficult search for new drugs is always challenged by the appearance of resistance.     

Novel alleles in classical major histocompatibility complex class II loci of the brushtail possum (<Emphasis Type="Italic">Trichosurus vulpecula</Emphasis>)

We have investigated the diversity of class II major histocompatibility complex (MHC) loci in the brushtail possum (Trichosurus vulpecula), an important marsupial pest species in New Zealand. Immunocontraceptive vaccines, a method of fertility control that employs the immune system to attack reproductive cells or proteins, are currently being researched as a means of population control for the possum. Variation has been observed in the immune response of individual possums to immunocontraceptives. If this variability is under genetic control, it could compromise vaccine efficacy through preferential selection of animals that fail to mount a significant immune response and remain fertile. The MHC is an important immune region for antigen presentation and as such may influence the response to immunocontraceptives. We used known marsupial MHC sequences to design polymerase chain reaction primers to screen for possum MHC loci. Alpha and beta chains from two class II families, DA and DB, were found in possums throughout New Zealand. Forty new class II MHC alleles were identified in the possum, and the levels of variability in the MHC of this marsupial appear to be comparable to those of eutherian species. Preliminary population surveys showed evidence of clustering/variability in the distribution of MHC alleles in geographically separate locations. The extensive variation demonstrated in possums reinforces the need for further research to assess the risk that such MHC variation poses for long-term immunocontraceptive vaccine efficacy.     

Biochemical and morphological evidence for host race evolution in desert mistletoe,Phoradendron californicum (Viscaceae)

Allozymes and morphological characters were used to test whether host race evolution—the genetic divergence of parasitic populations caused by adaptation to different host species—has occurred in desert mistletoe,Phoradendron californicum. Populations ofPhoradendron californicum from two hosts,Acacia greggii andProsopis glandulosa, were surveyed from the Mojave and Colorado deserts. Electrophoretic data indicated genetic differentiation of mistletoes occurring on these hosts. Three of four morphological characters (internode length, main shoot lateral shoot diameter ratio and berry color) also showed significant host-specific differentiation. These data support the hypothesis that host race formation has occurred or is occurring in this parasitic angiosperm.     

Genetic variability of plant characters in the partial inbreeder Collinsia heterophylla (Scrophulariaceae)

Quantitative genetic variability for six characters was estimated in four populations of the annual plant, Collinsia heterophylla, with estimated selling rates ranging from 0.36 to 0.68. Based on large samples of parental plants, all four populations showed significant genetic variation for two or more characters, and there was no sign that the more selfing populations had lower amounts of genetic variance or lower heritability values. Autogamous fruit set rates in the absence of pollinators also showed significant heritability in one population.     

Parasitism by Cuscuta pentagona attenuates host plant defenses against insect herbivores

Considerable research has examined plant responses to concurrent attack by herbivores and pathogens, but the effects of attack by parasitic plants, another important class of plant-feeding organisms, on plant defenses against other enemies has not been explored. We investigated how attack by the parasitic plant Cuscuta pentagona impacted tomato (Solanum lycopersicum) defenses against the chewing insect beet armyworm (Spodoptera exigua; BAW). In response to insect feeding, C. pentagona-infested (parasitized) tomato plants produced only one-third of the antiherbivore phytohormone jasmonic acid (JA) produced by unparasitized plants. Similarly, parasitized tomato, in contrast to unparasitized plants, failed to emit herbivore-induced volatiles after 3 d of BAW feeding. Although parasitism impaired antiherbivore defenses, BAW growth was slower on parasitized tomato leaves. Vines of C. pentagona did not translocate JA from BAW-infested plants: amounts of JA in parasite vines grown on caterpillar-fed and control plants were similar. Parasitized plants generally contained more salicylic acid (SA), which can inhibit JA in some systems. Parasitized mutant (NahG) tomato plants deficient in SA produced more JA in response to insect feeding than parasitized wild-type plants, further suggesting cross talk between the SA and JA defense signaling pathways. However, JA induction by BAW was still reduced in parasitized compared to unparasitized NahG, implying that other factors must be involved. We found that parasitized plants were capable of producing induced volatiles when experimentally treated with JA, indicating that resource depletion by the parasite does not fully explain the observed attenuation of volatile response to herbivore feeding. Collectively, these findings show that parasitic plants can have important consequences for host plant defense against herbivores.     

Comparing Evolvability and Variability of Quantitative Traits

There are two distinct reasons for making comparisons of genetic variation for quantitative characters. The first is to compare evolvabilities, or ability to respond to selection, and the second is to make inferences about the forces that maintain genetic variability. Measures of variation that are standardized by the trait mean, such as the additive genetic coefficient of variation, are appropriate for both purposes. Variation has usually been compared as narrow sense heritabilities, but this is almost always an inappropriate comparative measure of evolvability and variability. Coefficients of variation were calculated from 842 estimates of trait means, variances and heritabilities in the literature. Traits closely related to fitness have higher additive genetic and nongenetic variability by the coefficient of variation criterion than characters under weak selection. This is the reverse of the accepted conclusion based on comparisons of heritability. The low heritability of fitness components is best explained by their high residual variation. The high additive genetic and residual variability of fitness traits might be explained by the great number of genetic and environmental events they are affected by, or by a lack of stabilizing selection to reduce their phenotypic variance. Over one-third of the quantitative genetics papers reviewed did not report trait means or variances. Researchers should always report these statistics, so that measures of variation appropriate to a variety of situations may be calculated.     

Does chemical aposematic (warning) signaling occur between host plants and their potential parasitic plants?

Aposematism (warning) signaling is a common defensive mechanism toward predatory or herbivorous animals, i.e., interactions between different trophic levels. I propose that it should be considered at least as a working hypothesis that chemical aposematism operates between certain host plants and their plant predators, parasitic plants, and that although they are also plants, they belong to a higher trophic level. Specific host plant genotypes emit known repelling chemical signals toward parasitic plants, which reduce the level of, slow the directional parasite growth (attack) toward the signaling hosts, or even cause parasitic plants to grow away from them in response to these chemicals. Chemical host aposematism toward parasitic plants may be a common but overlooked defense from parasitic plants.     

The effects of mating system and genetic variability on susceptibility to trematode parasites in a freshwater snail, Lymnaea stagnalis

The amount and distribution of genetic variability in host populations can have significant effects on the outcome of host-parasite interactions. We studied the effect of mating system and genetic variability on susceptibility of Lymnaea stagnalis snails to trematode parasites. Mating system of snails from eight populations differing in the amount of genetic variability was manipulated, and self- and cross-fertilized offspring were exposed to naturally occurring trematode parasites in a controlled lake experiment. Susceptibility of snails varied between populations, but mating-system treatment did not have a significant effect. Heterozygosity of snails was negatively correlated with the probability of trematode infection, however, suggesting that parasitic diseases may pose a serious threat to populations lacking genetic variability.     

Host influence on floral variability inOrthocarpus densiflorus (Scrophulariaceae)

This study investigates the influence of host plants on the expression of floral variability in the hemiparasiteOrthocarpus densiflorus (Scrophulariaceae), to determine if interaction with host plants can facilitate the expression of normally hidden genes. Style extension inO. densiflorus is highly uniform in natural populations, with less than 1% of the individuals exhibiting an aberrant extended-style condition. Both seed treatment with giberellic acid and parasitic development with host plants significantly facilitates the expression of extended-style in progenies that show only minimal expression when grown autotrophically. Artificial selection experiments demonstrate the range of potential phenotypic variation to be under genetic control, and differentially influenced by the host environment. Although the biochemical basis of the host influence is unknown, some host plants produce stimuli that apparently disrupt buffering inO. densiflorus and expose normally unexpressed genetic variability to selection. If variation in other traits is similarly affected, the influence of host chemistry may provide parasitic plants with a greater than normal opportunity for rapid selectional change.     

Toward next-generation sequencing of mitochondrial genomes — Focus on parasitic worms of animals and biotechnological implications

Helminths (worms) include parasitic nematodes (roundworms) and platyhelminths (flatworms). These worms are abundant, and many of them are of agricultural, aquacultural, veterinary and medical importance and cause substantial socioeconomic losses worldwide. The genetic characterization of parasitic nematodes using advanced molecular tools is central to the diagnosis of infections and the control of parasitism. The accurate analysis of genetic variation also underpins studies of their taxonomy, epidemiology and evolutionary history. Although the nuclear genome contains suitable genetic markers (e.g., in ribosomal DNA) for the identification of many species, the large size and high variability of the mt genome consistently provides a rich source of such markers for informative systematic and epidemiological studies both within and among species. There is significant value in establishing a practical platform for the rapid sequencing, annotation and analysis of mt genomic datasets to underpin such fundamental and applied studies of parasitic worms (= helminths). In the last decade, there have been some important advances in the mt genomics of helminths, but next-generation sequencing (NGS) technologies now provide opportunities for high throughput sequencing, assembly and annotation. In this article, we provide a background on mt genomics, cover technological challenges and recent advances, and provide a perspective on future mt genome research of parasitic helminths and its fundamental scientific and biotechnological implications.     

Genetics of Life History in DROSOPHILA MELANOGASTER. I. Sib Analysis of Adult Females

A sib analysis of adult life-history characters was performed on about twelve hundred females from a laboratory Drosophila melanogaster population that had been sampled from nature and cultured so as to preserve its genetic variability. The following results were found. There was no detectable trend with age in additive or dominance genetic variances for age-specific fecundity. Environmental variance for age-specific fecundity increased with age. The genetic variance for fecundity characters was primarily additive. The genetic variance for longevity was primarily dominance variance. There were negative genetic correlations between early fecundity and lifespan, as well as between mean egg-laying rate and longevity.     

肿腿蜂类寄生蜂室内控害效能评价——以松脊吉丁肿腿蜂为例

为了开发利用天敌资源防治害虫,科学而客观地评价肿腿蜂对蛀干害虫的控害作用,研究了松脊吉丁肿腿蜂(Sclerodermus sp.)对松褐天牛3龄幼虫的功能反应,建立了肿腿蜂类寄生蜂室内控害效能评价体系,并证明了其可行性。该评价体系包括供试虫源标准、寄生蜂生物学与寄生行为学观察、寄生蜂对寄主的功能反应和寻找寄主效应以及寄生蜂的忠岐指数(Y)4个部分。研究结果表明:松脊吉丁肿腿蜂具有较强的控害潜力,单头雌成虫能防治3—4头松褐天牛3龄幼虫,21d内最多可致死9.07头寄主幼虫;寄主密度对单头寄生蜂寄生作用功能反应的测定结果与对寄生作用寻找效应的测定结果以及对产卵量影响的测定结果一致;综合评价该蜂对松褐天牛3龄幼虫控制效能,释放比为1∶1(即1头肿腿蜂雌蜂:1头3龄松褐天牛幼虫)时最高,其忠岐指数Y为39.63,这可能是肿腿蜂类天敌特有的抚幼习性所致,结论也与寄生蜂生物学特性及寄生行为学观察结果相同。研究结论证明该评价体系是稳定可靠的。评价体系在利用天敌昆虫生物防治害虫时为筛选最佳寄生性天敌种类提供了可行的方法和依据。     

Differential susceptibility to Brugia pahangi infection in Mongolian gerbils (Meriones unguiculatus) of different coat colour

The influence of intraspecific host variables on the response to parasitic infections is an important aspect of host-parasite relationships, yet little is known about this aspect of filariasis for lack of a model. This study presents coat colour mutants of the Mongolian gerbil (Meriones unguiculatus) as potential new models for research into the effects of host genetic variation on response to filarial infection. Peak level of microfilaraemia, eosinophil response, body weight and degree of splenomegaly in gerbils infected with Brugia pahangi varied with agouti, albino, and black coat colour. These results suggested that coat colour-related genes might influence host immune response to developmental stages of the parasite and eosinophil-mediated reaction might cause host damage.     

药物基因组学对癌症化疗的启示

药物基因组学的研究任务是阐明个体差异的遗传基础,并利用这些遗传信息来预测药物的疗效、毒性和安全性。绝大多数的癌症化疗药物在治疗效果及正常组织毒性上的个体差异一直广为关注。不仅诸多临床因素(如年龄、性别、饮食、药物相互作用等)与药物反应和治疗效果有关,而且药物分布(转运和代谢)和药物靶标的遗传变异同样可导致癌症治疗上的差异。本篇综述主要讨论当前和将来药物基因组学在临床癌症治疗和抗癌药物研制方面的应用。     

Assessing non-metric skeleton characters as a morphological tool

The appearance of non-metric skeletal characters in vertebrates results mainly from basic genetic control, as proved and documented for house mice and humans. Although the heritability of non-metric traits, mainly the presence of foramina and similar structures for blood vessels and nerves or dental occlusal variants, have been evaluated as rather low, the simultaneous consideration of several traits allows estimation of epigenetic variation in time and space as a result of genetic relationship. Thus, the main use of non-metric characters has been aimed at assessing epigenetic variability and divergence among populations. Applications extend from the problem of genetic isolation of populations, the lack of reproductive contact, detection of genetic drift, systematic studies to clarify species taxonomy, to phylogenetic interpretation.

Additionally, non-directional deviations from bilateral symmetry in non-metric characters, e.g. fluctuating asymmetry, could be caused by current environmental conditions in general. Fluctuating asymmetry is regarded as a measure of developmental instability to indicate the presence of genomic changes or the influence of contamination and/or habitat deterioration, and is also used as a further population parameter with integrated information. However, standpoints on the use of fluctuating asymmetry are quite inconsistent, fluctuating themselves between considering it a powerful biomonitoring tool to being merely a curious scientific toy.     

A variable-response model for parasitoid foraging behavior

An important factor inducing variability in foraging behavior in parasitic wasps is experience gained by the insect. Together with the insect's genetic constitution and physiological state, experience ultimately defines the behavioral repertoire under specified environmental circumstances. We present a conceptual variable-response model based on several major observations of a foraging parasitoid's responses to stimuli involved in the hostfinding process. These major observations are that (1) different stimuli evoke different responses or levels of response, (2) strong responses are less variable than weak ones, (3) learning can change response levels, (4) learning increases originally low responses more than originally high responses, and (5) hostderived stimuli serve as rewards in associative learning of other stimuli. The model specifies how the intrinsic variability of a response will depend on the magnitude of the response and predicts when and how learning will modify the insect's behavior. Additional hypotheses related to the model concern how experience with a stimulus modifies behavioral responses to other stimuli, how animals respond in multistimulus situations, which stimuli act to reinforce behavioral responses to other stimuli in the learning process, and finally, how generalist and specialist species differ in their behavioral plasticity. We postulate that insight into behavioral variability in the foraging behavior of natural enemies may be a help, if not a prerequisite, for the efficient application of parasitoids in pest management.