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Results for “genetic offset”

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PubMed2005

Effect of extended diapause on evolution of resistance to transgenic Bacillus thuringiensis corn by northern corn rootworm (Coleoptera: Chrysomelidae).

We develop a population genetics model for the northern corn rootworm, Diabrotica barberi Smith & Lawrence, to examine the effect of extended diapause on the evolution of resistance to transgenic Bacillus thuringiensis (Bt) corn, Zea mays L. We model conditions found in the center of the extended diapause problem along the Minnesota-South Dakota-Iowa borders. The proportion of resistance alleles in eggs oviposited after 15 simulated years is used to measure the evolution of resistance. Sensitivity analysis indicates that although population genetics parameters (fecundity, initial egg density, density-dependent larval survival, random mating, insecticide mortality, and gene expression) affect the evolution of resistance, product characteristics (e.g., Bt toxin dose) and farmer management practices (e.g., insecticide use on refuge corn and rotation pattern) generally have a larger impact on the development of resistance. Exceptions to this generalization exist: 1) if the resistance allele is dominant, resistance evolves quickly; 2) the level of random mating is an important determinant of how quickly resistance evolves for a theoretical high dose product; and 3) small differences in insecticide mortality imply large differences in resistance for medium- and low-dose products with high levels of Bt corn adoption and a predominance of 1- and 2-yr corn rotations. When extended diapause spreads into a new area, it typically reduces resistance to Bt corn, assuming Bt corn is used only on continuous corn. In the study region where extended diapause already exists, increasing extended diapause (increasing hatch rates after two or three winters while holding total hatch constant), tends to increase resistance because the resistance increasing effect of the hatch rate after two winters dominates the resistance decreasing effect of the hatch rate after three winters. However, this is not always the case, because combinations of rotation pattern, toxin dose, and soil insecticide use exist for which the net effect of extended diapause decreases resistance. Results are interpreted as a combination of two offsetting effects. First, extended diapause injects older alleles with lower resistance allele frequencies into the breeding population, which slows resistance. Second, extended diapause speeds the population's recovery from perturbations (reduces the undercompensating density dependence of population dynamics), which accelerates resistance.

Animals↗
PubMed1976

Realized and potential neutralization of mutant genes in man by nutritional selection.

Inborn errors of metabolism are examples of monogenic disease in man that, more often than not, impair adaptation. Appropriate modification of the nutritional environment has been used in several instances to offset the phenotypic effects of the mutant allele, with resultant relaxation of selection. Despite an impressive, if brief, record of its efficacy, nutritional treatment of inborn errors of metabolism remains suboptimal in the absence of relevant and superior food technology and well-established systems for its application to the patient. Some of the more commonly encountered multifactorial diseases are likely to yield in the future to the type of genetic analysis that has been effective for monogenic disease. Delineation of various monogenic subsets in a multifactorial disease profile may permit the application of specific treatment to persons in the universal population at particular risk with the disease. Coronary heart disease is an example of a major disease burden now undergoing such delineation, which may benefit from the assignment of specific nutritional and pharmacological treatment for particular forms of the disease.

Genetic Engineering↗
PubMed1989

Genetic segregation and the maintenance of sexual reproduction.

Sexual reproduction confronts evolutionary biology with a paradox: other things being equal, an asexual (all-female) population will have twice the reproductive potential of a competing sexual population and therefore should rapidly drive the sexual population to extinction. Thus, the persistence of sexual reproduction in most life forms implies a compensatory advantage to sexual reproduction. Work on this problem has emphasized the evolutionary advantages produced by the genetic recombination that accompanies sexual reproduction. Here we show that genetic segregation produces an advantage to sexual reproduction even in the absence of an advantage from recombination. Segregation in a diploid sexual population allows selection to carry a single advantageous mutation to a homozygous state, whereas two separate mutations are required in a parthenogenetic population. The complete fixation of advantageous mutations is thus delayed in a heterozygous state in asexual populations. Calculation of the selective load incurred suggests that it may offset the intrinsic twofold reproductive advantage of asexual reproduction and maintain sexual reproduction in diploid populations.

Animals↗
PubMed2002

Alphaviral gene transfer in neurobiology.

Semliki Forest virus (SFV), Sindbis virus (SIN), and Venezuelan equine encephalitis virus are simple, enveloped plus-strand RNA viruses belonging to the Alphavirus genus of the Togaviridae family. They have been developed into expression vectors that infect a wide host cell range and cause rapid and high-level transgene expression. Their easy and fast generation, classification into biosafety levels 1 and 2, and preferential transduction of neurons in cell and tissue cultures makes them an increasingly used gene transfer system. This review summarizes the alphaviral replication and expression, the replicon system, and its application in neurobiology. Alphaviral vectors can introduce multiple transgenes into host cells, and mutants with low or absent cytotoxicity and increased or decreased transgene expression levels are available. Temperature-dependent mutants permit to control the host cell specificity as well as the on- and offset of gene expression. These features, together with the transduction characteristics revealed in a direct comparison of alphaviral and other viral vectors in hippocampal slice cultures, make SFV and SIN vectors a powerful tool for neurobiological studies.

Alphavirus↗
PubMedDate not supplied

Modeling and advanced control of recombinant Zymomonas mobilis fed-batch fermentation.

This work presents the development of an unstructured kinetic model incorporating the differing degrees of product, substrate, and pH inhibition on the kinetic rates of ethanol fermentation by recombinant Zymomonas mobilis CP4:pZB5 for growth on two substrates. Product inhibition was observed to start affecting the specific growth rate at an ethanol concentration of 20 g/L and the specific productivity at about 35-40 g/L. Specific growth rate was also shown to be more sensitive to inhibition by lowered pH as well. A model for the inhibition of two competing substrates' cellular uptake via membrane transport is proposed. Inhibition functions and model parameters were determined by fitting experimental data to the model. The model was utilized in a nonlinear model predictive control (NMPC) algorithm to control the product concentration during fed-batch fermentation to offset the inhibitory effects of product inhibition. Using the optimal feeding policy determined online, the volumetric productivity of ethanol was improved 16.6% relative to the equivalent batch operation when the final ethanol concentration was reached.

Algorithms↗
PubMed1992

The colorectal cancer gene hunt: current findings.

Identification of four genes, each with its own clinical significance, promises probes for early diagnosis of colorectal cancer in the near future. It also suggests possibilities for new forms of chemotherapy to offset the effects of mutated or lost genes. Given the "moving target" of metastasis, this is likely to be a more fruitful approach than gene replacement--and a more immediate one.

Adenomatous Polyposis Coli↗
PubMed2003

Pregnancy and lactation: physiological adjustments, nutritional requirements and the role of dietary supplements.

Nutritional needs are increased during pregnancy and lactation for support of fetal and infant growth and development along with alterations in maternal tissues and metabolism. Total nutrient needs are not necessarily the sum of those accumulated in maternal tissues, products of pregnancy and lactation and those attributable to the maintenance of nonreproducing women. Maternal metabolism is adjusted through the elaboration of hormones that serve as mediators, redirecting nutrients to highly specialized maternal tissues specific to reproduction (i.e., placenta and mammary gland). It is most unlikely that the heightened nutrient needs for successful reproduction can always be met from the maternal diet. Requirements for energy-yielding macronutrients increase modestly compared with several micronutrients that are unevenly distributed among foods. Altered nutrient utilization and mobilization of reserves often offset enhanced needs but sometimes nutrient deficiencies are precipitated by reproduction. There are only limited data from well-controlled intervention studies with dietary supplements and with few exceptions (iron during pregnancy and folate during the periconceptional period), the evidence is not strong that nutrient supplements confer measurable benefit. More research is needed and in future studies attention must be given to subject characteristics that may influence ability to meet maternal and infant demands (genetic and environmental), nutrient-nutrient interactions, sensitivity and selectivity of measured outcomes and proper use of proxy measures. Consideration of these factors in future studies of pregnancy and lactation are necessary to provide an understanding of the links among maternal diet; nutritional supplementation; and fetal, infant and maternal health.

Adaptation, Physiological↗
PubMed1998

Evolution of immunologic functions of the mammary gland and the postnatal development of immunity.

Physiologic delays in production of immune factors occur in mammals including Homo sapiens. This finding is counter to a basic tenet of biologic evolution, because such delays increase the risk of infections. The disadvantage is, however, offset by defense factors in milk of the species in whom the developmental delay occurs. Reciprocal relationships between the production of immune factors by the lactating mammary gland and the production of those defense agents during early infancy are found in all investigated mammalian species. Thus, the evolution of these processes is closely related. Certain immunologic components of milk are highly conserved, whereas others vary according to the species. The variations most likely evolved by genetic mutations and natural selection. In addition, the immune composition of mammalian milks is associated with developmental delays in the same immunologic agents. Furthermore, most closely related mammals, such as humans and chimpanzees, are most similar in the defense agents in their milks and the corresponding developmental delays in their immune systems. Defense factors in human milk include antimicrobial agents (secretory IgA, lactoferrin, lysozyme, glycoconjugates, oligosaccharides, and digestive products of milk lipids), antiinflammatory factors (antioxidants, epithelial growth factors, cellular protective agents, and enzymes that degrade mediators of inflammation), immunomodulators (nucleotides, cytokines, and antiidiotypic antibodies), and leukocytes (neutrophils, macrophages, and lymphocytes). Because of a lack of geographic/ethnic variation in the immunologic composition of human milk and corresponding immunologic delays in infants, these evolutionary processes seem stable. This is supported by investigations of diverse populations that indicate that this evolutionary outcome is highly beneficial to human infants.

Animals↗
PubMed1992

Genetically determined differences in the antagonistic effect of pressure on ethanol-induced loss of righting reflex in mice.

Hyperbaric exposure antagonizes ethanol's behavioral effects in a wide variety of species. Recent studies indicating that there are genetically determined differences in the effects of body temperature manipulation on ethanol sensitivity suggested that genotype might also influence the effects of hyperbaric exposure on ethanol intoxication. To investigate this possibility, ethanol injected long sleep (LS)/Ibg (2.7 g/kg), short sleep (SS)/Ibg (4.8 g/kg), 129/J (2.9 g/kg), and C57BL/6J (3.6 g/kg) mice were exposed to one atmosphere absolute (ATA) air or to one or 12 ATA helium-oxygen (heliox) at ambient temperatures selected to offset ethanol and helium-induced hypothermia. Hyperbaric exposure significantly reduced loss of righting reflex (LORR) duration in LS, 129, and C57 mice, but not in SS mice. A second experiment found that hyperbaric exposure significantly reduced LORR duration and increased the blood ethanol concentration (BEC) at return of righting reflex (RORR) in LS mice, but did not significantly affect either measure in SS mice. These results indicate that exposure to 12 ATA heliox antagonizes ethanol-induced LORR in LS, 129 and C57 mice, but not in SS mice. Taken with previous results, the present findings suggest that the antagonism in LS, 129, and C57 mice reflects a pressure-induced decrease in brain sensitivity to ethanol and that the lack of antagonism in SS mice cannot be explained by pressure-induced or genotypic differences in ethanol pharmacokinetics.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

Effects of genetic variations in the dystonia protein torsinA: identification of polymorphism at residue 216 as protein modifier.

Four naturally occurring sequence variations have been found in the coding region of the DYT1 gene encoding torsinA. One of these, a 3 bp (DeltaGAG) deletion, underlies dominantly inherited cases of early-onset torsion dystonia. Others, including a single nucleotide polymorphism that replaces aspartic acid (D) at residue 216 with histidine (H) in 12% of normal alleles and two other rare deletions, have not been clearly associated with disease. To gain insight into how these sequence variations affect torsinA, we used the structure of the related protein ClpB to provide a model of torsinA's AAA+ domain. Motifs important for ATP hydrolysis-sensor 1 and sensor 2-were identified, mutagenized and used to validate predictions of this model. Inspection revealed that the DeltaGAG deletion associated with dystonia removes one residue from an alpha-helix in the C-terminal portion of the AAA+ domain. The resulting distortion in torsinA structure may underlie this mutant's known tendency to produce ER-derived inclusions as well as its proposed loss of function. The D/H polymorphism at residue 216 falls in the N-terminal portion of the AAA+ domain near the sensor 1 motif. Surprisingly, cells expressing torsinA with the polymorphic histidine developed inclusions similar to those associated with DeltaGAG-torsinA, indicating that this change may also affect torsinA structure. Introducing H216 into DeltaGAG-torsinA reduced its tendency to form inclusions, suggesting that the two changes offset each other. Our findings point to a structural basis for the defects associated with the disease-linked DeltaGAG deletion in torsinA. They also suggest possible connections between the allelic polymorphism at residue 216 and the penetrance of DYT1 dystonia, as well as a possible role for this polymorphism in related disease states.

Adenosine Triphosphatases↗
PubMed1987

Sensitive techniques for the detection of genetic variation in human isozymes.

The principal means by which genetic variation of enzyme proteins has been revealed is the physicochemical separation of isozymes in an electrical field followed by their specific detection. This approach is widely applicable to all types of species and almost every conceivable kind of tissue homogenate or protein secretion. In the human organism alone the products of more than 200 enzyme loci have been investigated by this means and more than 40 genetically determined human isozyme polymorphisms have been identified. Much of this progress has been achieved by the use of conventional gel electrophoresis methods and isozyme detection schemes that depend on enzyme-catalyzed conversion of substrate into chromogens or other types of visible product. However, the functional isozyme detection systems are often of limited sensitivity and are dependent on the good condition of the biological material under analysis and the retention of adequate enzyme activity. Also in some cases, especially where the final product of the detection reaction is not an insoluble compound, the staining may be so diffuse as to offset the high resolving power of the most effective protein separation methods such as isoelectric focusing in ultranarrow pH gradients. The recent development of alternative protein detection methods based on immunoblotting offers a new general approach to isozyme analysis and overcomes some of the limitations of isozyme detection by functional staining methods. The immunoblot methodology is applicable to proteins separated electrophoretically on denaturing gels and on native gels, including proteins separated by isoelectric focusing, and the fidelity of the high-resolution separation techniques appears to be preserved for most proteins by passive or electroblot transfer to nitro-cellulose filters. Furthermore this approach provides considerable flexibility in the sensitivity and the nature of the final reporter signal that is employed. For example, the reporter signal can be amplified by the use of appropriate intermediate reagents to provide a level of detection sensitivity for isozyme proteins which should, even with the present procedures, be far in excess of that which is obtained even by the best functional isozyme staining system. Also the use of an evanescent reporter system such as chemiluminescence may allow multiple analyses of the same immunoblot and hence examination of several different isozyme systems by sequentially using different primary antibodies.

Gene Amplification↗
PubMed1997

Skeletal effects of menstrual disturbances in athletes.

This article reviews the skeletal effects and clinical implications of menstrual disturbances in active women. At the lumbar spine, menstrual disturbances are associated with premature bone loss or failure to reach peak bone mass, while appendicular sites are less affected. This suggests that trabecular bone is more sensitive to hormonal stimuli and less responsive to mechanical loading than cortical bone. Although the mechanisms responsible for the detrimental effects of menstrual disturbances are likely to be multifactorial, low circulating levels of oestrogen are thought to be the main cause. The clinical significance of menstrual disturbances depends upon a number of factors, including type of sport, genetic background, body composition and calcium intake. Not all athletes who present with menstrual disturbances will develop osteopenia. Nevertheless, the risk of stress fracture does seem to be increased in athletes with menstrual disturbances and with lower bone density. Whether athletes with menstrual disturbances are at a greater risk for osteoporosis in later life is not yet known. Bone loss can be at least partially reversed, especially with the spontaneous resumption of menses. This may serve to offset any previous increased risk of osteoporosis. Furthermore, other factors, apart from low bone mass, act to determine the likelihood of osteoporotic fractures. Therefore, the clinical significance of menstrual disturbances associated with exercise participation needs to be established for each individual athlete. Bone densitometry may guide the clinician in this respect and assist in the formulation of appropriate management strategies.

Bone Density↗
PubMed1991

Loss of intensity-induced inhibition in inferior colliculus neurons leads to audiogenic seizure susceptibility in behaving genetically epilepsy-prone rats.

The genetically epilepsy-prone rat (GEPR) exhibits elevated seizure sensitivity and audiogenic seizures (AGS). The inferior colliculus (IC) is the most critical brain region for AGS initiation. The present study evaluated IC neuronal firing and convulsive behavior simultaneously in freely moving GEPRs. High intensity acoustic stimulation produces neuronal firing reductions (intensity-induced inhibition) in about 50% of IC neurons in normal rats. However, in GEPR IC neurons, intensity-induced inhibition is significantly less effective than normal. Offset inhibition is also reduced in GEPR IC neurons, which leads to a greater than normal incidence of offset (afterdischarge) responses at high stimulus intensities. At AGS onset most IC neurons exhibit burst firing and reductions of acoustically evoked neuronal responses. Responsiveness to acoustic stimuli returns following AGS. This change in IC neuronal firing pattern suggests that the network that governs IC neuronal firing has temporarily changed from the auditory system to the network that mediates seizure propagation. GABA is strongly implicated in intensity-induced, binaural, and offset inhibition in IC neurons. The diminished efficacy of these forms of GABA-mediated acoustically evoked inhibition in the GEPR IC extends previous results, showing reduced effectiveness of exogenously applied GABA and benzodiazepine in GEPR IC neurons. This reduced effectiveness of GABA-mediated inhibition along with excess excitant amino acids in GEPR IC, previously reported, appear to be vital neurotransmitter mechanisms, subserving the exaggerated output of IC neurons at high acoustic intensities. This exaggerated IC firing may be instrumental in seizure initiation in this epilepsy model.

Acoustic Stimulation↗
PubMed2001

Familial advanced sleep phase syndrome.

BACKGROUND: The circadian rhythms of sleep propensity and melatonin secretion are regulated by a central circadian clock, the suprachiasmatic nucleus of the hypothalamus. The most common types of sleep disorders attributed to an alteration of the circadian clock system are the sleep/wake cycle phase disorders, such as delayed sleep phase syndrome and advanced sleep phase syndrome (ASPS). Advanced sleep phase syndrome is characterized by the complaint of persistent early evening sleep onset and early morning awakening. Although the complaint of awakening earlier than desired is relatively common, particularly in older adults, extreme advance of sleep phase is rare. OBJECTIVE: To phenotypically characterize a familial case of ASPS. METHODS: We identified a large family with ASPS; 32 members of this family gave informed consent to participate in this study. Measures of sleep onset and offset, dim light melatonin onset, the Horne-Ostberg morningness-eveningness questionnaire, and clinical interviews were used to characterize family members as affected or unaffected with ASPS. RESULTS: Affected members rated themselves as "morning types" and had a significant advance in the phase of sleep onset (P<.001) and offset (P =.006) times. The mean sleep onset was 2121 hours for the affected family members and 0025 hours for the unaffected family members. The mean sleep offset was 0507 hours for the affected members and 0828 hours for the unaffected members. (Times are given in military form.) In addition, the phase of the circadian rhythm of melatonin onset for the affected family members was on average 3-1/2 hours earlier than for the unaffected members. CONCLUSIONS: The ASPS trait segregates with an autosomal dominant mode of inheritance. The occurrence of familial ASPS indicates that human circadian rhythms, similar to those in animals, are under genetic regulation. Genetic analysis of familial sleep and circadian rhythm disorders is important for identifying a specific gene(s) responsible for the regulation of sleep and circadian rhythms in humans.

Adult↗
PubMed1981

Evoked potentials in albinos: efficacy of pattern stimuli in detecting misrouted optic fibers.

Misrouting of retinogeniculostriate projections associated with retinal hypopigmentation has been found to be a general phenomenon in mammals, including humans. Anomalous optic pathway projections of albinos may be detected by recording visually evoked potentials (VEPs). To determine the efficacy of various stimulus conditions for detecting misrouted optic fibers, we compared flash, modulated light, pattern reversal and pattern onset/offset (appearance/disappearance) stimuli. Pattern onset/offset were found superior in detecting anomalies of misrouting of retinogeniculostriate projections. As a group, humans with retinal hypopigmentation have poor evoked potentials to offset and pattern reversal stimuli. Nystagmus seems to be most symptomatic of poor pattern reversal responses. In general onset/offset pattern stimuli are more versatile for detection of abnormalities in the visual system than pattern reversal stimuli.

Adolescent↗
PubMed2005

H2A- and H2E-derived CD4+CD25+ regulatory T cells: a potential role in reciprocal inhibition by class II genes in autoimmune thyroiditis.

We recently described a novel H2E class II-transgenic model (A(-)E(+)) of experimental autoimmune thyroiditis (EAT) that permits disease induction with heterologous thyroglobulin (Tg), but unlike conventional susceptible strains, precludes self-reactivity to autologous mouse Tg. In transgenic E(+)B10 (A(+)E(+)) mice, the presence of endogenous H2A genes is protective against H2E-mediated thyroiditis, inhibiting EAT development. The suppressive effect of H2A genes on H2E-mediated thyroiditis mirrors previous reports of H2E suppression on H2A-mediated autoimmune diseases, including EAT. The mechanism of the reciprocal-suppressive effect between class II genes is unclear, although the involvement of regulatory T cells has been proposed. We have recently reported that CD4(+)CD25(+) regulatory T cells mediate peripheral tolerance induced with mouse Tg in CBA mice. To determine whether these cells play a role in our E(+)-transgenic model, we first confirmed the existence of CD4(+)CD25(+) T cells regulating thyroiditis in E(+)B10.Ab(0) (A(-)E(+)) and B10 (A(+)E(-)) mice by i.v. administration of CD25 mAb before EAT induction. The depletion of CD4(+)CD25(+) T cells enhanced thyroiditis induction in the context of either H2E or H2A. Moreover, reconstitution of CD4(+)CD25(+) T cells from naive B10 mice restored resistance to EAT. E(+)B10 (A(+)E(+)) mice were also depleted of CD4(+)CD25(+) T cells before the challenge to determine their role in thyroiditis in the presence of both H2A and H2E genes. Depletion of CD4(+)CD25(+) regulatory T cells offset the suppression of H2E-mediated thyroiditis by H2A. Thus, these regulatory T cells may be involved in the reciprocal-suppressive effect between class II genes.

Adoptive Transfer↗
PubMed2001

Detecting and measuring senescence in wild birds: experience with long-lived seabirds.

This paper points out and discusses several practical and methodological problems that arise in attempts to detect and measure senescent declines in survival or breeding performance of wild animals, with specific emphasis on long-lived seabirds. Birds have no anatomical markers of age, so studies of age-related biology require marking individuals at the time of hatching and following them throughout their lives. Seabirds live longer than the working lifespan of biologists, and longer than the turnover times of study techniques or theories of senescence. Seabirds are exposed to changing environmental and demographic conditions and cannot be assumed to be in demographic equilibrium. Sample sizes of the oldest age-classes are always small, requiring either marking very large numbers of birds at hatching or continuing studies of old birds over many years. Incomplete sampling requires the use of mark-recapture models that have only been developed in the last 20years. Mortality selection resulting from demographic heterogeneity (selective survival of high-quality individuals) can offset or confound the effects of senescent changes within individuals. Many of these problems are amenable to solution and will be probably solved within a few years. In the meantime, this paper recommends that reviewers should be cautious about accepting published reports of senescent declines in natural populations.

Aging↗
PubMed1996

Mutations in the gene for human dihydrofolate reductase: an unlikely cause of clinical relapse in pediatric leukemia after therapy with methotrexate.

Resistance to methotrexate (MTX) in some sublines of mammalian cells is reported to be due to one of the following amino acid substitutions in dihydrofolate reductase (DHFR) that lower inhibition by MTX: Gly15 to Trp, Leu22 to Arg or Phe or Phe31 to Trp or Ser. We have produced variants of human DHFR (hDHFR) with these substitutions by directed mutagenesis. Recombinant hDHFR variants expressed in Escherichia coli have greatly decreased inhibition by MTX, but decreased catalytic efficiency, and in one case decreased stability. When a retroviral vector encoding wild-type (wt) hDHFR or one of these variants was introduced into murine fibroblasts or bone marrow progenitors, modest protection from MTX was conferred, even by wt. Relapsed pediatric patients with acute lymphoblastic leukemia who have received multiple courses of high-dose MTX seem most likely to develop such MTX resistance. cDNA was reverse transcribed from blast mRNA from 17 of these patients. However, upon amplification and sequencing of DHFR cDNA, no resistance mutation was found. The explanation for this probably lies in the need for considerable gene amplification to offset lowered catalytic efficiency, and the need for two-base changes for most substitutions, both of which are probably infrequent events.

Adolescent↗