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PubMed2000

Comparison of restricted maximum likelihood and method R for estimating heritability and predicting breeding value under selection.

Method R and Restricted Maximum Likelihood (REML) were compared for estimating heritability (h2) and subsequent prediction of breeding values (a) with data subject to selection. A single-trait animal model was used to generate the data and to predict breeding values. The data originated from 10 sires and 100 dams and simulation progressed for 10 overlapping generations. In simulating the data, genetic evaluation used the underlying parameter values and sires and dams were chosen by truncation selection for greatest predicted breeding values. Four alternative pedigree structures were evaluated: complete pedigree information, 50% of phenotypes with sire identities missing, 50% of phenotypes with dam identities missing, and 50% of phenotypes with sire and dams identities missing. Under selection and with complete pedigree data, Method R was a slightly less consistent estimator of h2 than REML. Estimates of h2 by both methods were biased downward when there was selection and loss of pedigree information and were unbiased when no selection was practiced. The empirical mean square error (EMSE) of Method R was several times larger than the EMSE of REML. In a subsequent analysis, different combinations of generations selected and generations sampled were simulated in an effort to disentangle the effects of both factors on Method R estimates of h2. It was observed that Method R overestimated h2 when both the sampling that is intrinsic in the method and the selection occurred in generations 6 to 10. In a final experiment, BLUP(a) were predicted with h2 estimated by either Method R or REML. Subsequently, five more generations of selection were practiced, and the mean square error of prediction (MSEP) of BLUP(a) was calculated with estimated h2 by either method, or the true value of the parameter. The MSEP of empirical BLUP(a) using Method R was greater than the MSEP of empirical BLUP(a) using REML. The latter statistic was closer to prediction error variance of BLUP(a) than the MSEP of empirical BLUP(a) using Method R, indicating that empirical BLUP(a) calculated using REML produced accurate predictions of breeding values under selection. In conclusion, the variability of h2 estimates calculated with Method R was greater than the variability of h2 estimates calculated with REML, with or without selection. Also, the MSEP of EBLUP(a) calculated using estimates of h2 by Method R was larger than MSEP of EBLUP(a) calculated with REML estimates of h2.

Animal Husbandry↗
PubMed2001

Consumer impressions of Tender Select beef.

With the recent development of technology to classify beef for tenderness, it is now possible for packers and retailers to market brands of beef known to be consistently tender. The present experiment was conducted to determine consumer impressions of Tender Select, a model beef brand comprised of cuts from tender U.S. Select carcasses. A telephone survey was conducted in metropolitan Denver, CO, to recruit consumers (n = 1,036) for this study. Consumers who met minimal limits for household income, age, and beef consumption were invited to participate in a beef shopping and usage study in a local supermarket. Point-of-purchase material was developed that described Tender Select as "the only steak guaranteed tender and lean." When shown a copy of the Tender Select concept card, 89% of participating consumers (n = 759) indicated that they would definitely or probably buy that product. Of those consumers that said they would buy the product, 35% indicated that their purchases of Tender Select would be in addition to their current fresh meat purchases. Most consumers (54.1%) indicated that if Tender Select was available at their grocery store, 1 or 2 of their next 10 purchases of beef cuts would be Tender Select. Sixty-five percent of consumers indicated that if a grocery store carried a line of beef cuts guaranteed to be tender, they would buy all of their beef at that store. Both strip loins from 104 U.S. Select beef carcasses, representing a broad range (8.7 to 43.4 kg; CV = 42%) in slice shear force (SSF) at 14 d postmortem, were used to determine the effect of SSF classification on consumer satisfaction and the correlation among trained sensory panel descriptive attribute ratings and in-home consumer ratings of beef longissimus steaks. Both trained sensory panelists and consumers rated low-SSF steaks higher than the high-SSF steaks for all traits (P < 0.001). All consumer traits (like, tenderness, juiciness, flavor like, flavor amount, and overall satisfaction) were more highly correlated with SSF and trained sensory panel tenderness ratings than with sensory panel flavor or juiciness ratings. These data show that tenderness is the primary determinant of satisfaction among consumers of U.S. Select top loin steaks and that a segment of consumers would pay a premium to purchase guaranteed-tender U.S. Select steaks.

Adult↗
PubMed2001

Increased plasma follicle-stimulating hormone concentrations in prepubertal gilts from lines selected for increased number of corpora lutea.

Plasma follicle-stimulating hormone (FSH) was evaluated in gilts from two studies in which ovulation rate was increased through direct selection for number of corpora lutea (CL) to determine whether selection for ovulation rate affected FSH secretion during prepubertal development. In the first study, 76 control and 110 selected gilts of University of Nebraska gene pool lines were bled twice during prepubertal development. Plasma FSH concentrations were greater (P < 0.05) at 53 (13.5%) and 75 (21.3%) d of age in selected than in control gilts. In the second study, 254 control gilts, 261 gilts from a line selected for ovulation rate, and 256 gilts from a line selected for uterine capacity were bled at three prepubertal ages. Plasma FSH was greater (P < 0.05), relative to controls, on d 34 (> 24%), 55 (> 13%), and 85 (> 10%) in White Composite gilts selected for either increased ovulation rate or for greater uterine capacity. Unilateral ovariectomy and hysterectomy were performed at 160 d of age on random gilts in these three lines (n = 377); weights of these organs were evaluated to determine whether selection affected their development. Ovarian and uterine weights were less (P < 0.01) in the control than in the ovulation rate line. Subsequently, ovulation rate was determined during pregnancy (n > or = 130 gilts/line). Controls had fewer (P < 0.01) CL (14.6) than gilts of the ovulation rate line (17.7) but numbers similar (P > 0.10) to those of gilts of the uterine capacity line (14.7). Within each line, plasma FSH only on d 85 correlated positively with subsequent ovulation rate (P < 0.03, 0.001, and 0.08; r = 0.17, 0.30, and 0.15 for control, ovulation rate, and uterine capacity lines, respectively). Ovarian weight at 160 d of age also correlated with subsequent ovulation rate (P < 0.03 and 0.001; r = 0.23 and 0.38) in control and ovulation rate gilts but not in uterine capacity gilts (P > 0.10; r = 0.11). Gilts selected for increased number of CL, in two independent studies, had greater concentrations of FSH during prepubertal development than respective controls. The modest but significant, positive association of FSH at 85 d of age with subsequent ovulation rate provides additional support for using plasma FSH in prepubertal gilts to indirectly select for ovulation rate.

Animals↗
PubMed1983

Performance of selected and control lines of Duroc and Yorkshire pigs and their reciprocal crossbred progeny.

Performance records for 223 boars and gilts in Duroc and Yorkshire selected and control lines and for 231 boar and gilt progeny from reciprocal breed crosses were analyzed to evaluate (1) maternal effects, (2) effects of mass selection in purebreds on performance of crossbred progeny and (3) heterosis effects. Selection of purebred herd replacements was based mainly on an index (Index) of average daily gain (ADG), average scan backfat thickness (BF) and scan longissimus muscle (loin eye) area (LEA) among tested pigs. Mixed models were fitted separately to the purebred and crossbred populations, including effects of breeding group, sires within breeding group, sex, pertinent interactions and residual on Index and its component traits, ADG, BF and LEA. Crossbred pigs from Yorkshire dams had slightly larger (P less than .10) LEA's and higher (P less than .05) Indexes, suggesting a small maternal effect favoring Yorkshire dams over Duroc dams in crosses of these breeds. Crossbred pigs from Yorkshire dams also had a higher ADG and slightly less BF than crossbred pigs from Duroc dams, but the differences were not significant. Selection differentials were over three times as large for sires as for dams in purebreds and were substantially larger in selected lines than in controls where selection pressure was essentially zero for ADG and Index. In parental purebreds, selected lines exceeded controls for ADG, LEA and Index and had less BF. Selected lines crossbred progeny exceeded control lines crossbred progeny for all traits including BF. Responses in crossbreds to purebred selection varied with the trait, suggesting effects of genetic correlations, gene frequency differences, nonadditive genetic variance and sampling variation. Heterosis appeared not to be influenced by performance level or intensity or direction of selection in parental purebreds.

Adipose Tissue↗
PubMed1991

Direct response in yield and correlated response in components accompanying selection for milk yield in Jerseys.

In 1967, the Jersey herd at the Dairy Experiment Station, Lewisburg, TN was divided into two groups on the basis of ancestry, type, and breeding value for milk as part of a project to determine effects of single trait selection for high milk yield on yield and correlated traits. Control group was mated randomly to 20 unproven young sires selected randomly from those available from breeding studs in 1967. Selection group was mated to sires selected solely on the basis of their high transmitting ability for milk. Selection sires were selected at intervals and used for 4 yr. By the end of the project (1984), lactation information was available on 672 daughters (520 selection and 152 control) of 37 bulls (17 selection and 20 control). Differences in breeding values for milk, fat, and fat test as calculated from the PTA reported in the July 1989 USDA genetic evaluations and differences in first lactation mature equivalent production of milk, fat, fat test, and 4% FCM were examined. Linear mixed models were used for all analyses and contained the fixed effects group, generation within group, and year. Sires were random, nested within group, and used to test for group differences. Groups differed for all traits. Selection was superior to control in breeding value for milk and fat (828 and 31 kg) and for production of milk, fat, and 4% FCM (1066, 42, and 1061 kg). Control was superior to selection in breeding value and production fat test (.15 and .12%). Group differences existed within generation class for all yield traits but not for fat percentage. Realized response closely matched or exceeded expected response as estimated from pedigree information.

Animals↗
PubMed1991

Genetic association of selection for increased leg muscle and increased shank diameter with body composition and walking ability.

Body compositions of a randombred control population (RBC2), a line selected for increased 16-wk BW (F), a line selected for increased shank diameter (FL), and a line selected for increased leg muscle mass (FM) were compared at 16 wk of age. The F line originated from the RBC2 population and the FL and FM lines were developed as sublines of the F line. The F and FL lines were developed through mass selection of BW and shank width, respectively. The FM line was developed through family selection for leg muscle mass. Selection for BW in the F line has resulted in an increase in the proportion of breast muscle and a decrease in the relative amount of leg bone in comparison with the RBC2 population. Selection for increased shank width in the FL line has increased not only shank weight but has produced concomitant increases in the weight of the tibiotarsal and femur bones. Although FL line has also shown a correlated increase in BW in association with increases in shank width the increase in leg bone weight was relatively greater than the increase in BW. Therefore, the relative weights of leg bones in the FL line increased such that they were more similar to the RBC2 population than to the F line. Although the amount of leg muscle increased slightly in the FM line, the relative proportion of leg muscle did not increase significantly. The selection program used was probably ineffective in increasing the proportion of leg muscle because of the high percentage (low selection intensity) of families selected and small family size for estimating family means.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

Molecular basis for functional maturation of thymocytes: increase in c-fos translation with positive selection.

In the process of positive selection, immature CD4+8+ double positive (DP) thymocytes expressing TCR reactive to self-MHC by appropriate avidity develop into mature thymocytes. Positive selection involves not only down-regulation of either CD4 or CD8 but also acquisition of immunocompetent potential such as cell proliferation and cytokine production. To understand the molecular basis for such functional maturation during the positive selection process, we examined whether nonselected DP, selected DP, and CD4+8- single positive thymocytes possess the activation potential for signaling pathways from mitogen-activated protein kinases (extracellular signal-regulated kinase and c-Jun N-terminal kinase) to AP-1. In response to stimulation, a marked induction of c-Fos protein expression as well as cell proliferation is detected only in CD4+8- single positive cells but not in selected and nonselected DP cells, though mitogen-activated protein kinase activities and c-fos transcripts are equally induced. In the presence of proteasome inhibitors, c-Fos protein became detectable in selected DP cells but still not in nonselected DP cells, suggesting that DP cells receiving positive selection signals acquire the capacity to translate the c-fos gene, but it may not be sufficiently high to overcome the degradation of c-Fos protein. These data indicate that the translating ability of the c-fos gene is up-regulated in the thymic positive selection process, from nonselected DP to CD4+8- single positive cells through positively selected DP cells. The distinguished responsiveness to stimulation in thymocytes with and without positive selection may be a result in part of the distinct regulation of the c-fos gene at the translational level.

Animals↗
PubMed2000

MEK activity regulates negative selection of immature CD4+CD8+ thymocytes.

CD4+CD8+ thymocytes are either positively selected and subsequently mature to CD4 single positive (SP) or CD8 SP T cells, or they die by apoptosis due to neglect or negative selection. This clonal selection is essential for establishing a functional self-restricted T cell repertoire. Intracellular signals through the three known mitogen-activated protein (MAP) kinase pathways have been shown to selectively guide positive or negative selection. Whereas the c-Jun N-terminal kinase and p38 MAP kinase regulate negative selection of thymocytes, the extracellular signal-regulated kinase (ERK) pathway is required for positive selection and T cell lineage commitment. In this paper, we show that the MAP/ERK kinase (MEK)-ERK pathway is also involved in negative selection. Thymocytes from newborn TCR transgenic mice were cultured with TCR/CD3epsilon-specific Abs or TCR-specific agonist peptides to induce negative selection. In the presence of the MEK-specific pharmacological inhibitors PD98059 or UO126, cell recovery was enhanced and deletion of DP thymocytes was drastically reduced. Furthermore, development of CD4 SP T cells was blocked, but differentiation of mature CD8 SP T cells proceeded in the presence of agonist peptides when MEK activity was blocked. Thus, our data indicate that the outcome between positively and negatively selecting signals is critically dependent on MEK activity.

Animals↗
PubMed2000

Intrinsic and extrinsic contributions to auditory selectivity in a song nucleus critical for vocal plasticity.

The development, maintenance, and perception of learned vocalizations in songbirds are likely to require auditory neurons that respond selectively to song. Neurons with song-selective responses have been described in several brain nuclei critical to singing, but the mechanisms by which such response properties arise, are modified, and propagate are poorly understood. The lateral magnocellular nucleus of the anterior neostriatum (LMAN) is the output of an anterior forebrain pathway (AFP) essential for learning and maintenance of song, processes dependent on auditory feedback. Although neurons throughout this pathway respond selectively to auditory presentation of the bird's own song, LMAN is the last stage at which responses to this auditory information could be transformed before being transmitted to vocal motor areas, where such responses may influence vocal production. Indeed, previous extracellular studies have indicated that LMAN's auditory selectivity is greater than that at earlier stages of the AFP. To determine whether LMAN local circuitry transforms or simply relays song-related auditory information to vocal control neurons, it is essential to distinguish local from extrinsic contributions to LMAN's auditory selectivity. In vivo intracellular recordings from LMAN projection neurons, coupled with local circuit inactivation, reveal that much of LMAN's song selectivity is supplied by its extrinsic inputs, but selective blockade of GABA receptors indicates that local inhibition is required for the expression of song selectivity. Therefore, LMAN neurons receive highly song-selective information, but LMAN's local circuitry can mask these selective inputs, providing a mechanism for context-dependent auditory feedback.

Acoustic Stimulation↗
PubMed2001

A general account of selection: biology, immunology, and behavior.

Authors frequently refer to gene-based selection in biological evolution, the reaction of the immune system to antigens, and operant learning as exemplifying selection processes in the same sense of this term. However, as obvious as this claim may seem on the surface, setting out an account of "selection" that is general enough to incorporate all three of these processes without becoming so general as to be vacuous is far from easy. In this target article, we set out such a general account of selection to see how well it accommodates these very different sorts of selection. The three fundamental elements of this account are replication, variation, and environmental interaction. For selection to occur, these three processes must be related in a very specific way. In particular, replication must alternate with environmental interaction so that any changes that occur in replication are passed on differentially because of environmental interaction. One of the main differences among the three sorts of selection that we investigate concerns the role of organisms. In traditional biological evolution, organisms play a central role with respect to environmental interaction. Although environmental interaction can occur at other levels of the organizational hierarchy, organisms are the primary focus of environmental interaction. In the functioning of the immune system, organisms function as containers. The interactions that result in selection of antibodies during a lifetime are between entities (antibodies and antigens) contained within the organism. Resulting changes in the immune system of one organism are not passed on to later organisms. Nor are changes in operant behavior resulting from behavioral selection passed on to later organisms. But operant behavior is not contained in the organism because most of the interactions that lead to differential replication include parts of the world outside the organism. Changes in the organism's nervous system are the effects of those interactions. The role of genes also varies in these three systems. Biological evolution is gene-based (i.e., genes are the primary replicators). Genes play very different roles in operant behavior and the immune system. However, in all three systems, iteration is central. All three selection processes are also incredibly wasteful and inefficient. They can generate complexity and novelty primarily because they are so wasteful and inefficient.

Behaviorism↗
PubMed2006

Faster lizards sire more offspring: sexual selection on whole-animal performance.

Sexual selection operates by acting on variation in mating success. However, since selection acts on whole-organism manifestations (i.e., performance) of underlying morphological traits, tests for phenotypic effects of sexual selection should consider whole-animal performance as a substrate for sexual selection. Previous studies have revealed positive relationships between performance and survival, that is, natural selection, but none have explicitly tested whether performance may influence reproductive success (through more matings), that is, sexual selection. Performance predicts dominance in some species, implying the effects of sexual selection, but how it does so has not been established, nor is it certain whether performance might be a by-product of selection for something else, for example, elevated circulating testosterone levels. We investigated the potential for sexual selection on sprint speed performance in collared lizards (Crotaphytus collaris), considering the potential mediating effects of circulating hormone levels. Among territorial, adult male collared lizards, only sprint speed significantly predicted territory area and number of offspring sired as determined by genetic paternity analysis. Body size, head size, and hind limb length had no effect. Neither plasma testosterone levels nor corticosterone levels correlated with sprint speed, territory area, or number of offspring sired. Thus, our results provide a direct link between whole-animal performance and reproductive success, suggesting that intrasexual selection can act directly on sprint speed performance and drive the evolution of underlying morphological traits.

Animals↗
PubMed1986

A quantitative method of analyzing the interaction of slightly selective radioligands with multiple receptor subtypes.

Subclasses of receptors exist for most neurotransmitters. Frequently, two subtypes of receptors coexist in the same tissue and, in some cases, they mediate the same physiological response. In tissues with two classes of binding sites for a given hormone, an estimate of the proportion of each class of binding sites is obtained by inhibiting the binding of a single concentration of a radioligand with a selective unlabeled ligand. Accurate estimates of the density of each class of receptors will only be obtained, however, if the radioligand is entirely nonselective. Selectivity of just 2- to 3-fold can markedly influence the results of subtype analysis. The conclusion that a radioligand is nonselective is usually based on the results of a saturation binding curve. If Scatchard analysis of such data results in a linear plot, then it is concluded that the radioligand is nonselective. However, Scatchard analysis cannot distinguish between a radioligand that is nonselective and one that is slightly selective. The use of a slightly selective radioligand can lead to errors of 50% or more, depending on the concentration of the radioligand relative to the Kd values of the two classes of sites. A new analytical method has been developed that can be used to quantitate 2- to 3-fold differences in the affinity of two distinct classes of binding sites for a radioligand. This new approach requires that a series of inhibition experiments with a selective unlabeled ligand be performed in the presence of increasing concentrations of the radioligand. Analysis of the resulting inhibition curves, utilizing the mathematical modeling program MLAB on the PROPHET system, yields accurate estimates of the density of each class of receptor as well as the affinity of each receptor for the labeled and unlabeled ligands. This approach was used to determine whether 125I-iodopindolol shows selectivity for beta 1- or beta 2-adrenergic receptors. A series of inhibition curves was generated with the unlabeled ligands ICI 89,406 (beta 1-selective) and ICI 118,551 (beta 2-selective), using membranes prepared from C6 glioma cells. These cells contain both beta 1- and beta 2-adrenergic receptors. 125I-Iodopindolol was determined to be 3-fold selective for beta 2-adrenergic receptors. Since the sensitivity of this approach is superior to that of Scatchard analysis, it is likely that other radioligands, previously thought to be nonselective, will be shown to be selective when analyzed by this method.

Adrenergic beta-Antagonists↗
PubMed1987

Statistical considerations of the random selection process in a drug-test program.

In a prospective drug-testing program, individuals whose job classifications have been defined as sensitive are placed in a selection pool. Periodically, individuals are chosen from this pool for drug testing. Random selection is a fair and impartial approach for this because each individual has an equal chance of being selected. Random selection also serves to reinforce the deterrent potential of a drug-testing program because individuals in the pool never know when or if they will be selected. This uncertainty discourages drug usage because of the risk involved in being selected and tested. A random selection process generates a Poisson distribution of probabilities that can be used to predict how many times an individual will be selected during a specific time interval. This information can be used to model the selection part of a drug-testing program to determine whether specific conditions of testing are met. For example, the probability of being selected a given number of times during the testing period can be minimized or maximized by varying the frequency of the sampling process. Consequently, the Poisson distribution and the mathematics governing it can be used to structure a drug-testing program to meet the needs of any given situation.

Employee Discipline↗
PubMed1979

Genetic analysis of antibody responsiveness to sheep erythrocytes in crosses between lines of mice selected for high or low antibody synthesis.

Two selective breedings of mice for minimal or maximal agglutinin response to heterologous erythrocytes were carried out (selection I and II). Preliminary reported data indicated that for both selections the heritability was between 0.18 and 0.36 and the number of relevant loci from 7--13. The results reported in this article are definitive since the data of ten to twenty generations at selection limit are available and large populations of interline hybrids F1, F2 and both backcrosses were analysed. The character 'high response' was partially dominant in F1 hybrids of both selections, the degree of this incomplete dominance was 0.27 in selection I and 0.54 in selection II. In selection I, 38% of the F2 variance was due to genetic factors (VG) and 62% to environmental effects (VE). The partition of phenotypic variance of F2 and backcrosses into additive variance (VA) and dominance variance (VD) was made according to three methods and the mean results were: VA = 0.72 and VD = 0.05. The resulting mean heritability was 0.35 and the number of relevant loci about ten. In selection II, 69% of the F2 variance was due to VG and 31% to VE. The three methods of variance calculation give somewhat discordant results. According to the more probable estimation (see discussion) VA = 0.95, the mean heritability was 0.23 and the number of loci, about 6. The results obtained in crosses between homologous lines of the two selections indicate that the two 'high' lines have probably identical homogeneous genetic constitution while the two 'low' lines contain some different 'high' effect loci.

Agglutinins↗
PubMed1984

Life-span, tumor incidence, and natural killer cell activity in mice selected for high or low antibody responsiveness.

Biozzi mice selected for high (H) or low (L) antibody responsiveness to natural antigens have been followed for their entire life-span to examine their pathology at death. As previously found in selection I, shorter life-span and higher lymphoma incidence were observed in L responder mice than in H responder mice selected for antibody responsiveness to sheep red blood cells (selection II). In mice selected for antibody responsiveness to Salmonella flagellar antigens (selection III), similar life-span and similar lymphoma incidence were found in H and L responder mice. Natural killer (NK) cell activity, as assessed in spleen cells from young mice, was lower in L than in H responder mice of selection I but higher in L than in H responder mice of both selections II and III. All these results indicate that longevity and lymphoma incidence at death are independent of NK cell activity in mice selected for H or L antibody responsiveness to natural antigens. Furthermore, genetic selection for antibody responsiveness does not always appear to influence life-span and lymphoma incidence.

Animals↗
PubMed1994

Selective uptake of high-density lipoprotein-associated cholesteryl esters by human hepatocytes in primary culture.

High-density lipoprotein cholesteryl esters are taken up by many cells without simultaneous uptake of high-density lipoprotein apolipoproteins. This selective uptake was investigated in human hepatocytes in primary culture. Human high-density lipoprotein-3 (density, 1.125 to 1.21 gm/ml) was radiolabeled in both its apolipoprotein and in its cholesteryl ester moiety; uptake of these high-density lipoprotein3 tracers by hepatocytes was investigated. Apparent high-density lipoprotein3 particle uptake as measured with the cholesteryl ester tracer was in excess of that from the apolipoprotein tracer, indicating selective uptake of high-density lipoprotein3 cholesteryl esters by hepatocytes. This selective uptake is a regulated pathway in hepatocytes, as demonstrated by an inverse relationship between cell cholesterol and the rate of selective uptake. Studies on the mechanism of selective uptake have used inhibitors such as monensin, chloroquine, heparin, and a monoclonal antibody directed against low-density lipoprotein receptors. These experiments provide no evidence for a role of cell-secreted apolipoprotein E, endocytosis or retroendocytosis in selective uptake. The intracellular fate of high-density lipoprotein3-associated cholesteryl esters was investigated with [3H]cholesteryl oleate-labeled high-density lipoprotein3. Hepatocytes hydrolyzed [3H]cholesteryl oleate internalized from labeled high-density lipoprotein3; this catabolism was not inhibited by the presence of chloroquine. In parallel hepatocytes were incubated with [3H]cholesteryl oleate-labeled low-density lipoprotein. Cells hydrolyzed [3H]cholesteryl oleate taken up with low-density lipoprotein; however, this hydrolysis was inhibited by chloroquine, indicating lysosomal low-density lipoprotein cholesteryl ester catabolism. These experiments show that high-density lipoprotein3 cholesteryl esters selectively taken up by hepatocytes are hydrolyzed independently from the classical lysosomal catabolic pathway. The question was addressed if selective uptake mediates a net mass uptake of cholesterol rather than an isotope exchange phenomenon. Incubation of hepatocytes with high-density lipoprotein-3 suppressed endogenous sterol synthesis from sodium [14C]acetate. Hepatocytes were incubated in the presence of high-density lipoprotein3; medium cholesteryl esters decreased as a result of incubation with hepatocytes. These results show a net mass delivery of high-density lipoprotein cholesteryl esters to hepatocytes. In conclusion, the pathway for selective uptake of high-density lipoprotein cholesteryl esters could be demonstrated in human hepatocytes in primary culture. A role for selective uptake in high-density lipoprotein-mediated cholesterol delivery to the liver in human beings in vivo is proposed.

Animals↗
PubMed1996

CD28 expression is not essential for positive and negative selection of thymocytes or peripheral T cell tolerance.

Thymocyte development requires positive selection of clones that can recognize Ag presented by MHC molecules and negative selection of clones that are self-reactive. However, the costimulatory signals required for negative selection and cell death, or positive selection and the transition to the peripheral lymphoid system, are not well understood. Many molecular interactions that are important for T cell activation have also been found to play a role in thymocyte development. The importance of the CD28/B7 interaction in the activation of mature T cells and recent observations that CD28 may play a role negative selection of developing CD4+CD8+ thymocytes suggest that CD28 may also be involved in development and maintenance of T cell tolerance. CD28-deficient mice were crossed to alpha beta and gamma delta TCR transgenic as well as H-2k Mlsc-bearing animals and were used to address the role of CD28 in positive and negative selection of developing T cells. The CD28-deficient animals demonstrated no obvious deficiency in either positive or negative selection of developing thymocytes. However, when mixed bone marrow chimeras were created with cells derived from both CD28-deficient and wild-type mice, the CD28+ T cells had a selective advantage over the CD28-deficient T cells. Therefore, it appears that CD28, although not essential for the selection of T cells during development, may allow for additional signals that increase the efficiency of selection and/or expansion of peripheral T cell populations.

Animals↗
PubMed1996

Potential role for retinoic acid receptor-gamma in the inhibition of breast cancer cells by selective retinoids and interferons.

Retinoids are known to inhibit the growth of a wide variety of cancer cells, including breast cancer cells. Advances made in recent years in the understanding of the molecular mechanisms of retinoid action have allowed the design of retinoids with selective activities. Such selective retinoids are of particular interest, because they may reduce the number of undesirable side effects observed with natural compounds. Here, we have compared the growth-inhibitory activities of natural retinoids with various selective retinoids, including anti-activator protein (AP)-1 selective compounds on estrogen receptor-positive and -negative breast cancer cell lines. In addition, we have investigated cooperativity between selective retinoids and IFNs and have begun to analyze the pathways that these two different growth inhibitors use for antagonizing breast cancer cell proliferation. We observe that several selective retinoids can inhibit breast cancer cells as efficiently as the natural compounds. Anti-AP-1-selective retinoids are as effective as retinoic acid receptor (RAR)-beta/gamma-selective compounds. This lets us conclude that retinoid-induced inhibition of breast cancer cell growth does not require retinoid receptor transactivation. Several synthetic retinoids including anti-AP-1-selective compounds show synergism with IFNs. However, true synergism between the two different types of growth regulators was seen only when both classes of molecules were used at low concentrations. RAR-beta/gamma and anti-AP-1-selective retinoids, but not RAR-alpha-selective compounds, induced increased RAR-gamma mRNA levels. Interestingly, IFNs at elevated concentrations (100 units/ml and higher) also induced increased RAR-gamma expression. Thus, when used at high concentrations, IFNs may activate growth-inhibitory pathways overlapping with those activated by retinoids. Because increased RAR-gamma expression is induced by the two different classes of breast cancer cell inhibitors, it is likely to have an important role in controlling the growth fo these cancer cells.

Antineoplastic Agents↗