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PubMed1997

Principles for the selection of doses in chronic rodent bioassays. ILSI Risk Science Working Group on Dose Selection.

Dose selection in chronic rodent bioassays has been one of the most debated issues in risk assessment. The Committee on Risk Assessment Methods of the National Research Council attempted, but failed, in 1993 to reach consensus on how to select doses for chronic rodent bioassays. However, a more recent effort conducted by the ILSI Risk Science Institute has resulted in a consensus set of principles for dose selection, including selection of the highest dose for chronic rodent bioassays. The principles encourage a move away from sole reliance on a maximum tolerated dose (MTD), as it has been traditionally defined (primarily by body weight and histopathology), and toward the use of sound scientific and toxicologic principles for the selection of all doses in the chronic bioassay. Specifically, the principles recommend that dose selection for chronic studies must be based on sound toxicologic principles; dose selection should consider human exposure; dose selection should be based on a variety of endpoints and effects derived from prechronic studies; and dose selection should consider physicochemical and other factors. Implementation of the principles internationally will have two important benefits; improvement in the quality and consistency of the rodent bioassay and international harmonization of dose selection procedures.

Animals↗
PubMed1999

REF Select: expert system software for selecting restriction endonucleases for restriction endonuclease fingerprinting.

REF Select, expert system software, has been developed to assist in the selection of optimal restriction endonucleases for restriction endonuclease fingerprinting (REF), a method for rapid and sensitive mutation screening of long DNA segments (1-2 kb). The REF method typically involves six separate digestions with up to two restriction endnonucleases used in each digestion. If done manually, performing a comprehensive review of the large number of possible sets of restriction endonucleases that could be used (over 10(19) in the example presented here) and making an optimal choice is not feasible. Furthermore, the typical nonoptimal manual selection takes approximately 8 h by someone experienced with REF. REF Select enables a comprehensive review of the possible sets and a consistent, objective and fast selection of an optimal set by using a two-step strategy: the selection of sets that meet specific constraints, which is followed by a ranking of those sets by an optimality score. Based on our experience with REF, we chose default selection and ranking parameters to help the user get started quickly. These parameters form a knowledge base that can be customized and then saved by the user. In conclusion, REF Select facilitates the general application of REF by serving as an expert system for the selection of optimal restriction endonucleases. We demonstrated REF Select using an example segment from the human p53 gene.

Algorithms↗
PubMed2002

A molecular marker for thymocyte-positive selection: selection of CD4 single-positive thymocytes with shorter TCRB CDR3 during T cell development.

The generation of the naive T cell repertoire is a direct result of maturation and selection events in the thymus. Although maturation events are judged predominantly on the expression of surface markers, molecular markers, more intimately involved in the selection process, can be informative. We have identified a molecular marker for selection in later stages of maturation in humans. Thymocytes are selected for the expression of TCR beta-chains with shorter CDR3 at the double-positive to single-positive (SP) transition. Here we extend these studies to the mouse and show that the selection phenotype is not related to alpha-chain pairing but is a function of the MHC haplotype. Interestingly, the selection is much more apparent in CD4 SP thymocytes than in CD8 SP cells. This is in contrast to human thymocytes, where the selection is equally apparent in both lineages. The involvement of MHC in the process argues that this is a positive selection stage. The difference in the extent of this selection between the two SP lineages may indicate a class difference in the nature of the TCR-MHC interaction, the role of coreceptors in the selection process, or both.

Animals↗
PubMed1972

Stabilizing and disruptive selection on a mutant character in Drosophila. IV. Selection on sensitivity to temperature.

Individual selection on temperature sensitivity was applied to the relative length of the 4th vein of the mutant ci(D-G) in four selection lines according to different selection schemes indicated in Figure 1. These selection systems include, besides the selection on temperature, disruptive selection. In all lines the disruptive component causes an increase of the phenotypic variance, but there are large differences in its composition. The selection changed temperature sensitivity in the expected direction in all lines. In one line (C-D(-)) however, the change in temperature sensitivity and the increase in variance were only small because the disruptive component and the canalizing component of the selection scheme restricted each others' effect. The results are discussed in relation to earlier results obtained by disruptive selection at one temperature.

Animals↗
PubMed1977

Mutation-selection balance with stochastic selection.

Diffusion theory has been used to analyze a model of mutation-selection balance in which the selection process is assumed to be stochastic in time. The limiting outcome of the mutation-stochastic selection process is determined qualitatively by the geometric mean fitnesses of the genotypes, and the conditions for fixation or polymorphism are similar to those that determine the outcome of the mutation-selection process when selection is constant. However, in the case of a completely recessive allele, detailed numerical study of the polymorphism associated with stochastic selection has shown that the average allele frequency maintained is greater than the equilibrium frequency expected when selection is constant, even when the geometric mean fitness of the recessive homozygotes is identical in the stochastic and deterministic models. Thus, allele frequencies in natural populations that are too high to be plausibly explained by a balance between mutation and constant selection can be accounted for if selection is stochastic.

Alleles↗
PubMed2004

Sexual selection, natural selection and the evolution of dimorphic coloration and ornamentation in agamid lizards.

Both sexual selection and natural selection can influence the form of dimorphism in secondary sexual traits. Here, we used a comparative approach to examine the relative roles of sexual selection and natural selection in the evolution of sexually dimorphic coloration (dichromatism) and ornamentation in agamid lizards. Sexual dimorphism in head and body size were used as indirect indicators of sexual selection, and habitat type (openness) as an index of natural selection. We examined separately the dichromatism of body regions "exposed to" and "concealed from" visual predators, because these body regions are likely to be subject to different selection pressures. Dichromatism of "exposed" body regions was significantly associated with habitat type: males were typically more conspicuously coloured than females in closed habitats. By contrast, dichromatism of "concealed" body regions and ornament dimorphism were positively associated with sexual size dimorphism (SSD). When we examined male and female ornamentation separately, however, both were positively associated with habitat openness in addition to snout-vent length and head SSD. These results suggest that natural selection constrains the evolution of elaborate ornamentation in both sexes as well as sexual dichromatism of body regions exposed to visual predators. By contrast, dichromatism of "concealed" body regions and degree of ornament dimorphism appear to be driven to a greater degree by sexual selection.

Animals↗
PubMed2006

Extreme rank selections for linkage analysis of quantitative trait loci using selected sib-pairs.

It is well known that linkage analysis using simple random sib-pairs has relatively low power for detecting quantitative trait loci with small genetic effects. The power can be substantially increased by using samples selected based on their trait values. Usually, samples that are obtained by truncation selection consist of random samples from a truncated trait distribution. In this article we propose an alternative method using extreme ranks for linkage analysis with selected sib-pairs. This approach approximates the truncation selection. With similar screening sizes and the same sample size of selected sib-pairs, the extreme rank selection and truncation method have similar power performance, both of which are substantially more powerful than when using random sib-pairs. Simulation results on the comparison of powers between the truncation selection and the extreme rank selection and/or random selection for linkage analysis are reported.

Genetic Linkage↗
PubMed1983

Reciprocal recurrent selection for 21-day litter weight of crossbred gilts. I. Selection applied and genetic change in reproduction of crossbred gilts.

Six cycles of reciprocal recurrent selection (RRS) between Line 8 (Duroc) and Line 9 (Beltsville No. 1) were completed at the Fort Reno Livestock Research Center, El Reno, Oklahoma. A randomly mated control line was maintained. Each cycle of selection required three seasons. Selection of purebred pigs (born in the second season) was based on the mean 21-d litter weight of their maternal and paternal half-sib crossbred gilts that were born in the first season and farrowed in the third season (XB21DLWT). On the average, 5.8 maternal and paternal half-sib gilts contributed to the mean XB21DLWT for each purebred individual. The average potential selection differential for XB21DLWT was 5.64 kg, but only 70.2% of this value was realized in the initial selection (3.95 kg). Disease problems and unsoundness were the primary reasons for this discrepancy. The potential, initial, final and weighted final standardized selection differentials for females averaged 61, 60, 55 and 47%, respectively, of the corresponding differentials for males. Standardized selection differentials were similar for Line 8 and Line 9. The estimate of realized heritability for XB21DLWT was .076 +/- .319 for the average of 8 X 9 and 9 X 8 gilts. Environmental trends, estimated from control data, were not significant for any of the traits evaluated. The genetic change in reproductive ability of 8 X 9, 9 X 8 and their unweighted average was estimated by regressing the deviation of the line mean from the control mean on generation number. In general, estimates of genetic change for litter size, litter weight and average pig weight/litter at 0, 21 and 42 d of age were not significant, but all estimates were favorable. The estimated genetic change for 21-d litter weight was 1.04 +/- 1.25 kg/cycle of selection. Based on these results and considering the complexity of RRS, the increase in generation interval and the expected decline in purebred performance that theoretically should accompany successful RRS, it seems doubtful that RRS can be more beneficial than selection based on purebred performance as a method to improve productivity of crossbred gilts.

Animals↗
PubMed2006

The DNA aptamers that specifically recognize ricin toxin are selected by two in vitro selection methods.

Aptamers which specifically recognize cytotoxin ricin were successfully selected using the two different in vitro selection methods. One selection method was used to isolate aptamers by affinity chromatography. Another selection method, named CE-SELEX, was carried out using CE as a separation approach. The high separation efficiency of CE evidently improved the rate of enrichment and obviously shortened the selection rounds, with near 87.2% binding just after the fourth round of selection. The aptamers A3, C1, and C5, derived from the two selection methods, were found to possess high affinity and specificity for ricin with the Kd values in the low nanomolar range, and did not recognize abrin toxin similar to ricin in the structures and properties, or BSA. Among the aptamers selected, A3 isolated by affinity chromatography shared extensive sequence similarity with C1 and C5 derived from CE-SELEX. They differed by only one base from each other. Their stable secondary structures predicted also had very similar structure motifs, and all folded a long and internal loop-embedded loop stem structure by base pairing. The ELISA and dot-blot analysis also proved that the selected DNA aptamers had the high specificity to ricin toxin.

Aptamers, Nucleotide↗
PubMed2006

Dual selection of a genetic switch by a single selection marker.

Forward engineering of synthetic genetic circuits in living cells is expected to deliver various applications in biotechnology and medicine and to provide valuable insights into the design principles of natural gene networks. However, lack of biochemical data and complexity of biological environment complicate rational design of such circuits based on quantitative simulation. Previously, we have shown that directed evolution can complement our weakness in designing genetic circuits by screening or selecting functional circuits from a large pool of nonfunctional ones. Here we describe a dual selection strategy that allows selection of both ON and OFF states of genetic circuits using tetA as a single selection marker. We also describe a successful demonstration of a genetic switch selection from a 2000-fold excess background of nonfunctional switches in three rounds of iterative selection. The dual selection system is more robust than the previously reported selection system employing three genes, with no observed false positive mutants during the simulated selections.

Computer Simulation↗
PubMed2005

Fish macronutrient selection through post-ingestive signals: effect of selective macronutrient deprivation.

Recent reports describe teleosts as being able to regulate energy intake by selecting from pure macronutrient sources, although the regulatory mechanisms involved in this selection remain unknown. The aim of the present work was to determine the effect of selective macronutrient deprivation on energy regulation and macronutrient selection, using for this purpose carbohydrate (CH), protein (P), and fat (F) packaged separately into gelatin capsules, a method that prevents the diet chemosensory properties at oropharyngeal level from interfering with macronutrient selection. Twenty-four individually housed sea bass (Dicentrarchus labrax) were subjected to two experiments: (a) two-macronutrient deprivation, and (b) one-macronutrient deprivation. In two-macronutrient deprivation, fish were fed sequentially with P, CH, or F, and in one-macronutrient deprivation, they were fed sequentially with two separately packaged macronutrients (P and CH, CH and F, or P and F). There was a rapid reduction of macronutrient intake in two-macronutrient deprivation, reaching 80% inhibition after 4, 5, and 7 days of P, CH, and F intake, respectively. In one-macronutrient deprivation, the energy intake was significantly reduced during selective F deprivation, but not with P or CH deprivation. Although the fish were being fed with only two macronutrients, the relative proportions of these macronutrients in each selective deprivation phase were the same as the baseline. These results show that in deprivation studies fish need at least F plus one other macronutrient to regulate their energy intake, and that their macronutrient selection is stable even when one is absent. In summary, fish seem to regulate energy and macronutrient selection through post-ingestive mechanisms probably involving chemosensory detection in the gut, and/or post-absorptive mechanisms.

Animal Feed↗
PubMed1996

Further evidence for differences between non-selective and BZ-1 (omega 1) selective, benzodiazepine receptor ligands in murine models of "state" and "trait" anxiety.

The behavioural effects of several BZ (omega) receptor ligands were compared in mice using the light/dark choice task, an animal model of "state" anxiety, and the free-exploration test, which has been proposed as an experimental model of "trait" anxiety. The drugs used included non-selective full (alprazolam, clorazepate, chlordiazepoxide and diazepam), partial agonists (bretazenil, imidazenil and Ro 19-8022) and BZ-1 (omega 1) selective receptor ligands (abecarnil, CL 218,872 and zolpidem). In the light/dark choice task, non-selective full agonists elicited clear anxiolytic-like effects increasing time spent in the lit box and simultaneously reducing attempts at entry into the illuminated cage followed by withdrawal responses, a measure of risk assessment. With the exception of abecarnil, both non-selective partial agonists and BZ-1 (omega 1) selective receptor ligands displayed reduced efficacy compared to the full agonists as they decreased risk assessment responses without altering time in the lit box. In addition, the weak anxiolytic-like actions displayed by selective BZ-1 (omega 1) agents were evident only at doses which reduced locomotor activity, indicating that this effect may be non-specific. In the free-exploration test, non-selective BZ (omega) receptor agonists markedly increased the percentage of time spent in the novel compartment and reduced the number of attempts to enter whereas selective BZ-1 (omega 1) receptor ligands displayed a weaker neophobia-reducing effect as they reduced risk assessment responses only. As was the case in the light/dark choice task, this latter effect was observed at locomotor depressant doses. These findings indicate that while both full and partial BZ (omega) receptor agonists are equally effective against "trait" anxiety, full agonists may be superior in reducing "state" anxiety. In addition, the lack of specific effects of selective BZ-1 (omega 1) receptor ligands in reducing both types of anxiety suggests that the BZ-1 (omega 1) receptor subtype cannot be considered as the primary target mediating the anxiolytic action of drugs interacting with the GABAA benzodiazepine receptor complex.

Animals↗
PubMed2004

Tracing sequence diversity change of RNA-cleaving deoxyribozymes under increasing selection pressure during in vitro selection.

In vitro selection has been used extensively over the past 10 years to create functionally diverse DNA enzymes. The majority of in vitro selection experiments to date have focused on the outcome rather than the process itself, a process that remains to be fully elucidated. In vitro selection techniques rely on the probability that some DNA molecules in a random-sequence library will fold into an appropriate tertiary structure and catalyze a desired reaction. Thus, sufficient sequence diversity in the DNA pool (and hence more catalytic DNA sequences) is a prerequisite for the successful isolation of efficient deoxyribozymes. The catalytic sequence diversity established by in vitro selection is governed largely by the choice of selection pressures, one of which is the length of the reaction time. The objective of this study was to evaluate the sequence diversity change of a pool of RNA-cleaving deoxyribozymes as a function of the reaction time. Seventeen rounds of in vitro selection were performed, and the reaction time was progressively decreased from 5 h to 5 s. A representative population from each time class was subsequently cloned and sequenced. A decline in sequence diversity was observed with decreasing reaction time, and the relationship appears to be logarithmic. In contrast, a control selection performed with a constant reaction time during each round led to a linear and comparatively very slow decrease in sequence diversity. This study provides the first methodical examination of the change in catalytic sequence diversity that occurs through the course of a deoxyribozyme selection experiment. Moreover, it represents a first step toward fully understanding the intricate pathway that lies between the beginning and end of an in vitro selection experiment.

Base Sequence↗
PubMed1990

Approaches to isozyme-specific inhibitors. 17. Attachment of a selectivity-inducing substituent to a multisubstrate adduct. Implications for facilitated design of potent, isozyme-selective inhibitors.

The synthesis is described of a methyl-C5' adduct of L-methionine and beta,gamma-ATP bearing a 6-S-n-Bu group in place of the 6-NH2 group of the parent adduct. The latter is a potent multisubstrate inhibitor in a model system consisting of the M-2 and M-T isozymes of rat methionine adenosyltransferase. When attached to ATP, the 6-S-n-Bu group induces selectivity for M-T inhibition by elevating affinity for the ATP site of M-T but not of M-2. In the above adduct it exerted a similar effect, expressed by selectivity and increased inhibitory potency toward M-T. This affords a second illustration of the ability of this approach to generate, relatively readily, a potent inhibitor with moderate isozyme selectivity. An overview is given of extensive evidence from the present series of studies that moderate (ca. 10-fold) isozyme selectivity is often exhibited by substrate derivatives bearing a single short substituent at a variety of atoms. This, together with features of another feasible approach to isozyme-selective inhibitor design, suggests an approach that has potential to facilitate the design of potent inhibitors that are both isozyme-selective and selective for a given metabolic conversion. It comprises (1) evaluation of the above type of substrate derivatives as inhibitors of a chemotherapeutically significant set of isozymes (target and nontarget), (2) attempted derivation of a potent multisubstrate adduct inhibitor of the isozymes, (3) attachment to such an adduct of one or more selectivity-inducing substituents revealed in the first step, and, if desired, (4) systematic modification of substituents with a view to obtaining enhanced potency and/or isozyme-selectivity.

Adenosine Triphosphate↗