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At least 649 records · Page 36Linked to original sources
PubMed2006

Invasion of pests resistant to Bt toxins can lead to inherent non-uniqueness in genetically modified Bt-plant dynamics: mathematical modeling.

Genetically modified crops are effective pest management tools for worldwide growers. However, there is a concern that pests may develop resistance to Bt-toxins produced by genetically modified Bt-plants. We study the impact of the Bt-resistant pests on Bt-crops. Furthermore, the dynamics of the Bt-plant-Bt-susceptible insects-Bt-resistant insects system is analysed and it is shown that throughout the insect reproduction period the plant biomass dynamics resulting from invasion of Bt-resistant insects is non-unique. Namely, the chaotic attractor and the limit cycle, which are responsible for the plant and insect biomass dynamics, are shown to coexist. As a result, the Bt-plant-Bt-resistant insect system can manifest either chaotic or regular oscillations of plant and insect biomass depending on spatial patterns resulting from invasion of Bt resistant insects into the Bt plant-Bt susceptible insect system. We show that the non-uniqueness of the system dynamics under unfavorable environmental conditions, such as in the so-called zones of risky agriculture in many developing countries and industrialized countries, can lead to essential decrease in the plant biomass.

Animals↗
PubMed2005

Bayesian implementation of a genetic model-free approach to the meta-analysis of genetic association studies.

A genetic model-free method for the meta-analysis of genetic association studies is described that estimates the mode of inheritance from the data rather than assuming that it is known. For a bi-allelic polymorphism, with G as risk allele and g as wild-type, the genetic model depends on the ratio of the two log odds ratios, lambda = log OR(Gg)/log OR(GG), where OR(GG) compares GG with gg and OR(Gg) compares Gg with gg. Modelling log OR(GG) as a random effect creates a hierarchical model that can be implemented within a Bayesian framework. In Bayesian modelling, vague prior distributions have to be specified for all unknown parameters when no external information is available. When the data are sparse even supposedly vague prior distributions may have an influence on the posterior estimates. We investigate the impact of different vague prior distributions for the between-study standard deviation of log OR(GG) and for lambda, by considering three published meta-analyses and associated simulations. Our results show that depending on the characteristics of the meta-analysis the results may indeed be sensitive to the choice of vague prior distribution for either parameter. Genetic association studies usually use a case-control design that should be analysed by the corresponding retrospective likelihood. However, under some circumstances the prospective likelihood has been shown to produce identical results and it is usually preferred for its simplicity. In our meta-analyses the two likelihoods give very similar results.

Bayes Theorem↗
PubMed2002

Genetic network modeling.

The inference of genetic interactions from measured expression data is one of the most challenging tasks of modern functional genomics. When successful, the learned network of regulatory interactions yields a wealth of useful information. An inferred genetic network contains information about the pathway to which a gene belongs and which genes it interacts with. Furthermore, it explains the function of the gene in terms of how it influences other genes and indicates which genes are pathway initiators and therefore potential drug targets. Obviously, such wealth comes at a price and that of genetic network modeling is that it is an extremely complex task. Therefore, it is necessary to develop sophisticated computational tools that are able to extract relevant information from a limited set of microarray measurements and integrate this with different information sources, to come up with reliable hypotheses of a genetic regulatory network. Thus far, a multitude of modeling approaches have been proposed for discovering genetic networks. However, it is unclear what the advantages and disadvantages of each of the different approaches are and how their results can be compared. In this review, genetic network models are put in a historical perspective that explains why certain models were introduced. Various modeling assumptions and their consequences are also highlighted. In addition, an overview of the principal differences and similarities between the approaches is given by considering the qualitative properties of the chosen models and their learning strategies.

Gene Expression Regulation↗
PubMed1995

Is homosexuality genetic? A critical review and some suggestions.

Genetic analysis of behavioral differences among human beings requires both careful experimental design and appropriate genetic models. Any genetic study must be (1) valid and precise measures of individual differences, (2) appropriate methods to ascertain biological relationships, (3) research subjects who have been randomly recruited, (4) appropriate sample sizes, and (5) appropriate genetic models to interpret the data. In addition, the researchers must exercise caution in interpreting biosocial effects from the observed phenotypic correlations. To date, all studies of the genetic basis of sexual orientation of men and women have failed to meet one or more or any of the above criteria.

Female↗
PubMed1987

Including the environment in models for genetic segregation.

Current models for linkage and segregation analysis do not allow for many of the different ways in which the environment may affect risk for a psychiatric disorder. A variety of mechanisms for the contribution of the environment and the correlation and interaction of environment effects with genetic differences are described. The approach to including these effects in models for segregation and linkage is outlined.

Genotype↗
PubMedDate not supplied

Paradigms and paradoxes: mouse (and human) models of genetic deafness.

Mouse models have proved valuable tools in the analysis of human genetic disorders. The identification of the genes mutated in classical mouse mutants and the analysis of the phenotype of mutants following targeted gene disruption have provided some clarification of the development and functioning of the inner ear. A number of these genes also play a role in human deafness. Analysis of mutations in both human and mouse deafness genes has identified a number of distinct phenomena that contribute to the observed phenotype.

Animals↗
PubMed2025

Rat somatic genome editing enables ER+ breast cancer modeling.

Genetically engineered mouse models have advanced cancer research but often fail to capture key features of certain human tumors. Rats, with distinct physiology and tumor biology, offer a powerful alternative, yet their use has been constrained by technical barriers to genome editing. Here, we report efficient somatic genome editing in rats, enabling both Indel and substitution mutations. We then apply this approach to model estrogen receptor (ER)-positive breast cancer, which accounts for ~70% of human cases but remains poorly represented in mice. The resulting rat tumors reproduce hallmarks of human ER+ breast cancer, including ductal histology, hormone responsiveness, and immune-microenvironmental features. By contrast, identical genetic alterations in mice failed to yield ER+ tumors, underscoring critical species differences in tumorigenesis. Together, this work establishes a versatile platform for rapid generation of clinically relevant rat tumor models, opening new avenues to dissect tumor biology, therapeutic response, and immune interactions in previously inaccessible cancer subtypes.

Journal Article↗
PubMed1989

Anthelmintic resistance and the control of ovine ostertagiasis: a drug action model for genetic selection.

A site-specific genetic prediction model is presented, which examines the influences of different anthelmintic treatment regimens on selecting for drug resistance within a sheep management system. The model exploits the power of modern microcomputers to integrate factors such as parasite strain, geographic location, management practice and genetic fitness to identify effective control regimens which do not lead to resistant Ostertagia circumcincta strains over a 30-year horizon. The potential use of the model as a farm level management-support tool is discussed.

Animals↗
PubMedDate not supplied

Genetic mouse models of extended lifespan.

Since 1996, seven genetic mouse models have been reported to show increased lifespan: Ames and Snell dwarf mice, the 'little mouse' (Ghrhr(lit/lit)), mice null for either growth hormone receptor/binding protein (GHR/BP(-/-)) or p66(shc) (p66(shc-/-)), mice heterozygous for the IGF-I receptor (Igf1r(+/-)), and fat-specific insulin receptor knockout mice. In this article, we describe and evaluate these mouse models with respect to their relevance for aging studies. While these seven genetic models all show a significant increase in lifespan, issues of sample size and animal husbandry procedures require further evaluation before firm conclusions can be drawn on the reproducibility of life extension in most of these mouse models. Because data on the age-related pathology and physiological functions are lacking for all of the models, except the dwarf mice, it is too early to conclude that aging is retarded in these mouse models. However, these mouse models are already providing new information about the mechanism underlying mammalian aging.

Aging↗
PubMed2005

Ballooning dispersal using silk: world fauna, phylogenies, genetics and models.

Aerial dispersal using silk ('ballooning') has evolved in spiders (Araneae), spider mites (Acari) and in the larvae of moths (Lepidoptera). Since the 17th century, over 500 observations of ballooning behaviours have been published, yet there is an absence of any evolutionary synthesis of these data. In this paper the literature is reviewed, extensively documenting the known world fauna that balloon and the principal behaviours involved. This knowledge is then incorporated into the current evolutionary phylogenies to examine how ballooning might have arisen. Whilst it is possible that ballooning co-evolved with silk and emerged as early as the Devonian (410-355 mya), it is arguably more likely that ballooning evolved in parallel with deciduous trees, herbaceous annuals and grasses in the Cretaceous (135-65 mya). During this period, temporal (e.g. bud burst, chlorophyll thresholds) and spatial (e.g. herbivory, trampling) heterogeneities in habitat structuring predominated and intensified into the Cenozoic (65 mya to the present). It is hypothesized that from the ancestral launch mechanism known as 'suspended ballooning', widely used by individuals in plant canopies, 'tip-toe' and 'rearing' take-off behaviours were strongly selected for as habitats changed. It is contended that ballooning behaviour in all three orders can be described as a mixed Evolutionary Stable Strategy. This comprises individual bet-hedging due to habitat unpredictability, giving an underlying randomness to individual ballooning, with adjustments to the individual ballooning probability being conferred by more predictable habitat changes or colonization strategies. Finally, current methods used to study ballooning, including modelling and genetic research, are illustrated and an indication of future prospects given.

Animals↗
PubMed2002

Estrogen receptors in skeletal metabolism: lessons from genetically modified models of receptor function.

Estrogens have long been known to be important for skeletal homeostasis, but their precise mechanisms of action in bone are still unclear. Mice with targeted deletions of the estrogen receptors alpha (ERalpha) and beta (ERbeta) have been generated by two research groups and several studies performed characterizing the phenotype of ERalpha knockout (ERKOalpha), ERbeta knockout (ERKObeta), or double deletion of ERalpha and ERbeta (DERKO) mice. Initial studies reported a reduction in bone mineral density in male ERKOalpha mice. More extensive analyses have been puzzling, likely because of compensatory mechanisms in ERKO mice. Furthermore, the existence of a third ER continues to be a potential explanation for some actions of estrogen in bone. Other rodent models, including the testicular feminized mouse and rat, the aromatase knockout mouse, and a rat with a dominant negative ER mutation, have added information regarding estrogen's actions in bone. This review summarizes many reports characterizing available rodent models with genetic alterations relevant to estrogen action. The sum of these reports suggests that the ERbeta is not highly protective in bone because loss of its function results in minimal alterations in the skeleton. Furthermore, loss of both the ERalpha and the ERbeta does not account for loss of estrogen action in bone, because the impact of DERKO is seemingly not as great as the impact of gonadectomy on the skeleton. Finally, through studies of ERKO mice and other rodent models of altered sex steroid action, it appears that estrogen may be more protective in the skeleton than androgens.

Androgen-Insensitivity Syndrome↗
PubMed1979

Rhesus monkey (Macaca mulatta) model in genetic toxicology mitomycin C clastogenicity in germ cells.

The value of rhesus monkeys (Macaca mulatta) as a genetic toxicology model is limited by their scarcity, expense, and impracticality of progeny testing. However, in some special circumstances, e.g., accidental exposure of humans to potential mutagens, rhesus monkeys or other primates may provide a superior animal model to help to cope with a difficult public health situation. Using the testis as a target organ we found that when primary spermatocytes were treated in pre-leptotene stage with 1 mg mitomycin C/kg body weight, the frequency of exchanges, fragments, sex-chromosome and autosomal univalents increased significantly at diakinesis-metaphase I. This response was absent in cells treated during diplotene, late pachytene or during spermatogonial stages. We suggested that animals should be evaluated not only for genetic toxicology parameters, but also toxicologically, histologically, behaviorally, for carcinogenesis and seminal cytology. Whenever possible, the animals should be recycled.

Animals↗
PubMed1993

Antihypertensive effect of a newly synthesized endothelin antagonist, BQ-123, in a genetic hypertensive model.

A newly synthesized ET(A)-selective antagonist, BQ-123, was examined with respect to its anti-endothelin(ET) action in vitro and in vivo and its effect on blood pressure in Wistar Kyoto rats (WKY), spontaneously hypertensive rats (SHR) and stroke-prone spontaneously hypertensive rats (SHRSP). In isolated porcine coronary arteries, BQ-123 (0.07 microM to 6.0 microM) shifted the concentration-response curve for ET-1 to the right without affecting the maximal response of ET-1, its pA2 value being 7.35. Intravenous infusion of BQ-123 at a rate of 1.2 and 30 mg/kg/hr produced a significant decrease in blood pressure in 20- to 29-week-old SHRSP, but did not alter blood pressure in 13- to 16-week-old WKY or in 18- to 19-week-old and 40-week-old SHR. The hypotensive effect of BQ-123 depended on the pretreatment blood pressure level. These results suggest that ET-1 is involved in part in the maintenance of high blood pressure in malignant hypertension, as exemplified by SHRSP.

Amino Acid Sequence↗
PubMed2004

Effects of rubral microinjections of muscimol and bicuculline in a genetic animal model of paroxysmal dystonia.

Previous studies suggested that GABAergic dysfunctions within the red nucleus are involved in stress-inducible paroxysmal dystonia of the dt(sz) mutant hamster. In the present study, rubral microinjections of the GABAA receptor agonist muscimol exerted only moderate antidystonic effects and the antagonist bicuculline failed to show significant effects on the severity of dystonia. These data indicate that disturbed rubral GABAergic inhibition is not important for the manifestation of dystonia in the dt(sz) mutant.

Animals↗
PubMed2005

Nitric oxide dynamics and endothelial dysfunction in type II model of genetic diabetes.

Although diabetes is a major risk factor for vascular diseases, e.g., hypertension and atherosclerosis, mechanisms that underlie the "risky" aspects of diabetes remain obscure. The current study is intended to examine the notion that diabetic endothelial dysfunction stems from a heightened state of oxidative stress induced by an imbalance between vascular production and scavenging of reactive oxygen/nitrogen species. Goto-Kakizaki (GK) rats were used as a genetic animal model for non-obese type II diabetes. Nitric oxide (NO) bioavailability and O2- generation in aortic tissues of GK rats were assessed using the Griess reaction and a lucigenin-chemiluminescence-based technique, respectively. Organ chamber-based isometric tension studies revealed that aortas from GK rats had impaired relaxation responses to acetylcholine whereas a rightward shift in the dose-response curve was noticed in the endothelium-independent vasorelaxation exerted by the NO donor sodium nitroprusside. An enhancement in superoxide (O2-) production and a diminuation in NO bioavailability were evident in aortic tissues of GK diabetic rats. Immunoblotting and high-performance liquid chromatography (HPLC)-based techniques revealed, respectively, that the above inverse relationship between O2- and NO was associated with a marked increase in the protein expression of nitric oxide synthase (eNOS) and a decrease in the level of its cofactor tetrahydrobiopterin (BH4) in diabetic aortas. Endothelial denudation by rubbing or the addition of pharmacological inhibitors of eNOS (e.g. N(omega)-nitro-L-arginine methyl ester (L-NAME)), and NAD(P)H oxidase (e.g. diphenyleneiodonium, apocynin) strikingly reduced the diabetes-induced enhancement in vascular O2- production. Aortic contents of key markers of oxidative stress (isoprostane F2alpha III, protein-bound carbonyls, nitrosylated protein) in connection with the protein expression of superoxide generating enzyme NAD(P)H oxidase (e.g. p47phox, pg91phox), a major source of reactive oxygen species in vascular tissue, were elevated as a function of diabetes. In contrast, the process involves in the vascular inactivation of reactive oxygen species exemplified by the activity of CuZnSOD was reduced in this diseased state. Our studies suggest that diabetes produces a cascade of events involving production of reactive oxygen species from the NADPH oxidase leading to oxidation of BH4 and uncoupling of NOS. This promotes the oxidative inactivation of NO with subsequent formation of peroxynitrite. An alteration in the balance of these bioactive radicals in concert with a defect in the antioxidant defense counteracting mechanism may favor a heightened state of oxidative stress. This phenomenon could play a potentially important role in the pathogenesis of diabetic endothelial dysfunction.

Animals↗
PubMed1999

A note on the power provided by sibships of sizes 2, 3, and 4 in genetic covariance modeling of a codominant QTL.

The contribution of size 3 and size 4 sibships to power in covariance structure modeling of a codominant QTL is investigated. Power calculations are based on the noncentral chi-square distribution. Sixteen sets of parameter values are considered. Results indicate that size 3 and size 4 sibships provided large increases in power over size 2 sibships. On average a size 3 (4) sibship is 3 (6 to 7) times as informative as a size 2 sibship. The increase in power does not depend on the specific effects sizes of the independent variables in the model. These findings extend results presented by Fulker and Cherny (1996) and Schork (1993). We consider the informativeness of the size 2, 3, and 4 sibships, which differ in the unique configuration of IBD sharing. Three of the 10 size 3 and 7 of the 36 size 4 sibships are particularly informative. The results presented concern random (unselective) sampling but do have implications for selective sampling.

Alleles↗
PubMed2003

Genetic animal models for absence epilepsy: a review of the WAG/Rij strain of rats.

Based on the reviewed literature and the data presented in this paper, conclusions can be drawn with respect to the validity of the WAG/Rij strain of rats as a model for absence epilepsy in humans. The view that the WAG/Rij model has "face validity" is supported by the simultaneous presence of clinical and electroencephalographic signs characterizing absences in rat and humans, by the decrease in responsiveness during the presence of spike-wave discharges in both species, by the agreement between model and patient with respect to the preferential occurrences of spike-wave discharges at transitions in states of vigilance, by the corresponding modulation of spike-wave discharges by physical and mental activities in both and, finally, by the fact that in both humans and rats absence epilepsy is inherited. Against this view, however, argue two points. In rats, absences appear after puberty and are maintained during life, while in humans the seizures occur before puberty and then disappear or convert to more serious forms of epilepsy. The second point is the frequency difference of the spikes and waves in the discharge train: 8-10 Hz in the rat and 3 Hz in the human (though there are no a priori reasons why the frequency of spike waves in the burst must be the same in all species). The absence model also has predictive validity, based on pharmacological data that demonstrate the specificity of certain drugs as being effective in convulsive epilepsies and not in absence epilepsy. So far, all drugs affect spike-wave activity the same way in rats and humans, with lamotrigine being, perhaps, the only exception. Furthermore, sleep deprivation is a powerful provocation for the initiation of spike-wave discharges in both rats and humans. Potential explanations for the presence of absence seizures in rats have been found at the levels of activities in networks and nuclei; of neurons, membrane properties, and ion channels; of proteins and enzymes; and, finally, of genes and chromosomes. Further descriptions of the cellular processes can be found extensively in the literature (e.g., McCormick and Contreras, 2001) and those of the thalamo-cortico-thalamic network in this review as well as in others (Avanzini et al., 1999). Considering the extensive involvement of the phenomena under study with theoretical issues such as the relationship between sleep spindles and spike-wave discharges, and the origin of seizure activity, it can be concluded that the model also has construct validity as far as the present neurobiological theories holding for absence epilepsy in humans are concerned. The WAG/Rij model can therefore be recommended for continued use in evaluating antiepileptic drugs for monotherapy and polytherapy, as well as for the toxicological side effects of putative new antiabsence drugs.

Age Factors↗