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PubMed1973

Effects of population size and selection intensity of short-term response to selection for postweaning gain in mice.

The effects of population size and selection intensity on the mean response was examined after 14 generations of within full-sib family selection for postweaning gain in mice. Population sizes of 1, 2, 4, 8 and 16 pair matings were each evaluated at selection intensities of 100% (control), 50% and 25% in a replicated experiment. Selection response per generation increased as selection intensity increased. Selection response and realized heritability tended to increase with increasing population size. Replicate variability in realized heritability was large at population sizes of 1, 2 and 4 pairs. Genetic drift was implicated as the primary factor causing the reduced response and lowered repeatability at the smaller population sizes. Lines with intended effective population sizes of 62 yielded larger selection responses per unit selection differential than lines with effective population sizes of 30 or less.

Analysis of Variance↗
PubMed1998

Genetic and economic responses for within-family marker-assisted selection in dairy cattle breeding schemes.

Marker-assisted selection schemes that utilize information about quantitative trait loci to preselect progeny test bulls within a family are the most practical application of quantitative trait loci results in the short-term. Technical difficulties exist for across-family marker-assisted selection using BLUP procedures. Two within-family marker-assisted selection schemes were evaluated genetically and economically using stochastic simulation for a locus that explained 5% of phenotypic variance. The genetic and economic impacts of variation in the number of offspring per bull-dam were evaluated. The top down marker-assisted selection scheme identifies sires that are heterozygous for the locus based on the granddaughter design and uses the quantitative trait locus information in the preselection of grandsons entering progeny testing. The bottom up marker-assisted selection scheme identifies sires heterozygous for a quantitative trait locus based on the daughter design and uses the information in the preselection of sons entering progeny testing. The top down scheme with one progeny per bull-dam reduced the rate of genetic gain compared with that from a breeding scheme that ignored knowledge of the quantitative trait locus. The top down scheme with reproductive performance of 3 or 40 progeny per bull-dam increased genetic gain by 1 to 2%. The bottom up scheme increased the rate of genetic gain by 1.5, 3.5, and 5% for 1, 3, and 40 progeny per bull-dam, respectively. When the top down scheme was used on the maternal path and the bottom up scheme on the paternal path, increases were 9% with 40 progeny per bull-dam. The use of reproductive technologies on bull-dams is imperative to prevent gains from marker-assisted selection being eroded by the loss in polygenic selection differential that results when more bull-dams are required to enable preselection of sons using markers.

Animals↗
PubMed1986

Smoking behaviour and personality patterns of smokers with low and high CO absorption.

The present experiment describes an attempt to select differentially nicotine dependent smokers by means of an objective and non-invasive measure of cigarette smoke CO absorption. Toward this goal the differences in expiratory tidal air CO concentration before and after smoking a single cigarette (tidal CO boost) were measured in three experimental sessions. The selection criteria were tidal CO boosts greater than 3.5 p.p.m. and less than 1 p.p.m. According to these criteria 19 out of 171 subjects were consistently found to be high CO absorbers and 20 were found to be low CO absorbers. Puffing behaviour was measured throughout all three test sessions by the flowmeter method and respiratory inhalation by thorax impedance plethysmography. In addition, heart rate was continuously measured during smoking. These data were used to assess for specific differences between the two extremes of inhalation behaviour. High CO absorbers differed from low CO absorbers by more intensive patterns of puffing and respiratory inhalation, by higher daily cigarette and coffee consumption, by lower alcohol consumption, by shorter latencies to the first cigarette in the morning, by greater subjective need for smoking and by lower scores for healthy eating habits. No intergroup differences were observed for smoking induced heart rate acceleration. The high CO absorbers were significantly older than the low CO absorbers; however, no evidence was found that any of the differences in smoking style between the two extremes might be related to their difference in age. No differences were seen in cigarette strengths, in personality or in coronary prone behaviour as assessed by means of standardized questionnaires in all subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1991

Mass selection for increased 200-day weight in a closed line of Landrace pigs.

Mass selection for increased weight at 200 d of age was conducted for six generations in a line of Landrace pigs. In the select line, the heaviest nine boars and 18 gilts were selected from each generation to produce the subsequent generation. A contemporaneous control line was maintained by randomly selecting a son from each sire and a daughter from each dam to attain a line size of five boars and 10 gilts. Inbreeding coefficients averaged .182 and .191 for the select- and control-line pigs and .150 and .162 for the select- and control-line dams, respectively, in the sixth generation. The 200-d weights and ultrasound backfat thickness data were collected from 1,022 pigs of 2,181 pigs farrowed. These pigs were sired by 92 boars and out of 210 sows. The generation interval was 13 mo. Twelve traits were studied: weights at birth and at 21, 35, 70, 154, and 200 d of age; daily gains from birth to 35 d, 35 to 70 d, 70 to 154 d, and 154 to 200 d; ultrasound backfat thickness at 200 d; and ultrasound backfat thickness adjusted for 200-d weight. Total weighted cumulative selection differential for 200-d weight was 88.7 kg. Realized heritability for 200-d weight was .26 +/- .08 with an average response of 4.2 +/- 1.3 kg/generation. Correlated responses resulted in increases for all weights and daily gains evaluated. Although ultrasound backfat thickness at 200 d increased in the select line compared to the control line, it was not altered by selection for 200-d weight when adjusted for 200-d weight.

Adipose Tissue↗
PubMedDate not supplied

Estimation of genetic variability and selection response for clutch length in dwarf brown-egg layers carrying or not the naked neck gene.

In order to investigate the possibility of using the dwarf gene for egg production, two dwarf brown-egg laying lines were selected for 16 generations on average clutch length; one line (L1) was normally feathered and the other (L2) was homozygous for the naked neck gene NA. A control line from the same base population, dwarf and segregating for the NA gene, was maintained during the selection experiment under random mating. The average clutch length was normalized using a Box-Cox transformation. Genetic variability and selection response were estimated either with the mixed model methodology, or with the classical methods for calculating genetic gain, as the deviation from the control line, and the realized heritability, as the ratio of the selection response on cumulative selection differentials. Heritability of average clutch length was estimated to be 0.42 +/- 0.02, with a multiple trait animal model, whereas the estimates of the realized heritability were lower, being 0.28 and 0.22 in lines L1 and L2, respectively. REML estimates of heritability were found to decline with generations of selection, suggesting a departure from the infinitesimal model, either because a limited number of genes was involved, or their frequencies were changed. The yearly genetic gains in average clutch length, after normalization, were estimated to be 0.37 +/- 0.02 and 0.33 +/- 0.04 with the classical methods, 0.46 +/- 0.02 and 0.43 +/- 0.01 with animal model methodology, for lines L1 and L2 respectively, which represented about 30% of the genetic standard deviation on the transformed scale. Selection response appeared to be faster in line L2, homozygous for the NA gene, but the final cumulated selection response for clutch length was not different between the L1 and L2 lines at generation 16.

Animals↗
PubMedDate not supplied

Teaching the differential diagnosis of common complaints to medical students.

Differential diagnosis of common complaints is a curricular area appropriate for family medicine. Not usually taught in medical school, it is an area in which family medicine faculty are competent and effective teachers. A new component of our sophomore family medicine seminars has been the use of cases that demonstrate problems in the differential diagnosis of common complaints and that illustrate important aspects of family medicine. Students are assigned textbook readings dealing with the differential diagnosis of the common complaint to be reviewed. For each seminar, a simulated patient is given a script dealing with a different common complaint. The student's task is to make the diagnosis and conduct an appropriate interview while being videotaped. We have also introduced a junior selective, "Differential Diagnosis of Common Complaints," that deals with 15 to 20 common complaints, rather than diseases. Both sophomore and junior students have particularly enjoyed the participatory and problem-solving aspects of the newly designed courses.

Curriculum↗
PubMed2005

Proteomic analysis of differentially expressed proteins between metastatic and non-metastatic human colorectal carcinoma cell lines.

OBJECTIVES: To explore the expressions of metastasis-related proteins between metastatic LS174T and non-metastatic SW480 human colorectal carcinoma cell lines. METHODS: Two-dimensional gel electrophoresis (2-DE) was applied to separate the total proteins of cells. The silver-stained gels were analysed by 2-DE software Image Master 2D Elite. Selected differential protein spots were identified with peptide mass fingerprinting based on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and database searching. RESULTS: The protein endothelial cell growth factor 1 (platelet-derived), rhotekin protein (RTKN), septin 1, cyclin-dependent kinase 1, sialic acid binding Ig-like lectin 11, tyrosinase-related protein-2, translin-like protein, and DNA directed RNA polymerase II polypeptide J-related gene isoform 2 appeared in metastatic but were not detected in non-metastatic cell lines, whereas integrin-linked kinase-associated protein phosphatase 2C isoform 2, MHC class I promoter binding protein, protein phosphatase 2A regulatory subunit B' (PR 53), carboxypeptidase A5, paired box transcription factor, zinc finger protein 79, and apolipoprotein B-48 were detected in non-metastatic but were absent in metastatic cell lines. In addition, cyclin fold protein 1 variant A and pre-B-cell leukemia transcription factor 1 were lowly expressed in the non-metastatic cell line and were significantly upregulated in the metastatic cell line. These identified proteins were involved in cell growth, motility, invasion, adhesion, apoptosis and tumour immunity, which is associated with distinct aspects of tumour metastasis. CONCLUSIONS: These data are valuable for the identification of differentially expressed proteins involved in human colorectal carcinoma carcinogenesis and metastasis.

Adenocarcinoma↗
PubMedDate not supplied

A method to optimize selection on multiple identified quantitative trait loci.

A mathematical approach was developed to model and optimize selection on multiple known quantitative trait loci (QTL) and polygenic estimated breeding values in order to maximize a weighted sum of responses to selection over multiple generations. The model allows for linkage between QTL with multiple alleles and arbitrary genetic effects, including dominance, epistasis, and gametic imprinting. Gametic phase disequilibrium between the QTL and between the QTL and polygenes is modeled but polygenic variance is assumed constant. Breeding programs with discrete generations, differential selection of males and females and random mating of selected parents are modeled. Polygenic EBV obtained from best linear unbiased prediction models can be accommodated. The problem was formulated as a multiple-stage optimal control problem and an iterative approach was developed for its solution. The method can be used to develop and evaluate optimal strategies for selection on multiple QTL for a wide range of situations and genetic models.

Animals↗
PubMed2002

International genetic evaluations of Holstein sires for milk somatic cell and clinical mastitis.

International genetic evaluations for milk somatic cell and clinical mastitis have been implemented on a routine basis by Interbull. This paper examines possible genetic consequences of such evaluations. Holstein data from 12 countries were used for this purpose. Trait definitions and national genetic evaluation procedures were first summarized and showed that differences between countries existed. Estimated genetic correlations among milk somatic cell in these countries ranged from 0.47 to 0.97, with a median of 0.88. Estimated genetic correlations among clinical mastitis in three Nordic countries ranged from 0.59 to 0.83, and estimated genetic correlations between clinical mastitis in the three Nordic countries and milk somatic cell in the non-Nordic countries ranged from 0.37 to 0.78 with a median of 0.55. Bulls without daughter information in the Nordic countries had low reliabilities on the Nordic clinical mastitis scales. International genetic evaluations for milk somatic cell and clinical mastitis enable a broader selection among foreign bulls, and higher selection differentials were found when using international evaluations compared with national evaluations.

Animals↗
PubMed2004

Genotype-assisted optimum contribution selection to maximize selection response over a specified time period.

Genotype-assisted selection (GAS), i.e. selection for an identified quantitative trait locus (QTL) and polygenic background genes, has been shown to increase short-term genetic gain but may reduce long-term genetic gains. In order to avoid this reduction of long-term gain, multi-generation optimization of truncation selection schemes is needed. This paper presents a multi-generation optimization of optimum contribution (OC) selection with selection on an identified QTL. This genotype-assisted optimum contribution (GAOC) selection method assumes that the optimum selection differential at the QTL is constant over the time horizon, and achieves this by controlling the increase of the frequency of the positive QTL allele. Implementation was straightforward by an additional linear restriction in the OC algorithm. GAOC achieved 35.2%, 2.3% and 1.1%, respectively, more cumulative genetic gain than OC selection (ignoring the QTL) using time horizons of 5, 10 and 15 generations. When one-generation optimization of GAS was used instead of multi-generation optimization, these figures were 2.8%, 3.1% and 3.2%, respectively. Simulated annealing was used to optimize the increases of the frequency of the positive QTL allele in order to test the optimality of GAOC. This latter resulted in genetic gains that were always within 0.4% of those of GAOC. In practice, short-term genetic gains are also important, which makes one-generation optimization of genetic gain closer to optimal.

Data Interpretation, Statistical↗
PubMed1977

Evaluation of the culling variate used by breeders in actual selection.

The theoretical basis and computational procedures for estimating the culling variate utilized by breeders in actual selection are presented. The essential part of this procedure is to derive the unknown culling variate in terms of a linear combination of traits based on realized indirect selection differentials of those traits and phenotypic variances and covariances among traits in the population. Special emphasis is placed on the distribution of the variables involved. The accuracy of the culling variates is estimated by use of the biserial correlation with some modifications. Numerical illustrations are given for different types of selection.

Animals↗
PubMed1987

Mineralocorticoid specificity of renal type I receptors: in vivo binding studies.

We have injected rats with [3H]aldosterone or [3H]corticosterone, plus 100-fold excess of the highly specific glucocorticoid RU 28362, with or without excess unlabeled aldosterone or corticosterone and compared type I receptor occupancy in kidney and hippocampus. Thirty minutes after subcutaneous injection [3H]aldosterone was well retained in renal papilla-inner medulla, renal cortex-outer medulla, and hippocampus; in contrast, [3H]corticosterone was well retained only in hippocampus. Competition studies for [3H]aldosterone binding sites showed corticosterone to be a poor competitor in the kidney compared with hippocampus. Time-course studies, with rats killed 10-180 min after tracer administration, showed very low uptake/retention of [3H]corticosterone by kidney; in hippocampus [3H]corticosterone retention was similar to that of [3H]aldosterone in kidney, and retention of [3H]aldosterone by hippocampus was much more prolonged than of either tracer in any other tissue. Studies in 10-day-old rats, with very low levels of corticosteroid binding globulin (CBG), showed a high degree of aldosterone selectivity in both zones of the kidney, whereas [3H]aldosterone and [3H]corticosterone were equivalently bound in hippocampus. We interpret these data as evidence for a mechanism unrelated to extravascular CBG conferring mineralocorticoid specificity on renal type I receptors and propose two models derived from our findings consistent with such differential selectivity.

Aldosterone↗
PubMed1999

Educating T cells: early events in the differentiation and commitment of cytokine-producing CD4+ and CD8+ T cells.

T lymphocytes acquire the ability to synthesize cytokines during their primary response to antigen, often giving rise to effector populations with a polarized type 1 or type 2 cytokine profile. However, polarization is not a simple choice between two differentiation pathways. This article reviews the evidence, particularly from single-cell and clonal studies, that polarization is the outcome of a series of stochastic events whose probabilities are determined in part by genetic background and in part by extracellular signals received during activation and clonal expansion. The data suggest that these extracellular signals independently and differentially regulate the probability of expression of each cytokine gene, for example by their effects on clonal expansion and chromatin remodeling, CpG demethylation and transcriptional activation of cytokine genes. Polarization is, therefore, achieved at the population level by altering frequencies of expression among cells with many different expression patterns, rather than by selective differentiation of a discrete subset. Type 1 and type 2 populations progressively lose responsiveness to counter-polarizing stimuli. While the molecular basis of this process is not yet known, the observed persistence of cells with flexible cytokine profiles in some polarized populations suggests that loss of flexibility may also be a probabilistic event.

Animals↗
PubMed2002

Differential screening-selected gene aberrative in neuroblastoma protein modulates inflammatory pain in the spinal dorsal horn.

Differential screening-selected gene aberrative in neuroblastoma (DAN) belongs to a novel gene family that includes the Xenopus head-inducing factor, Cerberus and the dorsalizing factor, Gremlin. It has been suggested that members of this family control diverse processes in growth, development and the cell cycle.Here, we demonstrate that the DAN protein is produced in the small neurons of the dorsal root ganglion and is transported to the nerve terminals in the spinal dorsal horn in adult rats. Furthermore, intrathecal injection of an antibody to the DAN protein suppressed inflammatory pain caused by the introduction of complete Freund's adjuvant or carrageenan into the rat hindpaw. The amount of mRNA for DAN in dorsal root ganglion neurons and of its expressed protein in the spinal dorsal horn were both increased in inflammatory models.Together, these data suggest that the DAN protein may be a novel neuromodulator in primary nociceptive nerve fibers.

Afferent Pathways↗
PubMed2005

Human embryonic stem cells: biology and clinical implications.

Embryonic stem cells (ESCs) are derived from the inner cell mass of the preimplantation stage embryo and are capable of prolonged symmetrical self-renewal (both daughter cells remain escs) as well as differentiation into derivatives of all three embryonic germ layers. ESCs therefore have the potential to provide an unlimited supply of transplantable cells to replace or regenerate damaged or diseased tissues. However, several barriers must be overcome before successful clinical trials are possible: for example, pure populations of the desired cell type need to be selected and expanded in clinically relevant numbers, and a method for preventing immunological rejection of the transplanted cells without long-term immunosuppressive therapy is also required. In this review, we highlight recent developments in human ESC derivation and expansion, outline current understanding of the signalling pathways underlying stem cell renewal, and discuss challenging problems related to the selective differentiation and immune properties of human ESCs.

Animals↗
PubMed1998

Docosahexaenoic acid promotes differentiation of developing photoreceptors in culture.

PURPOSE: The purpose of this work was to study the effects of diverse fatty acids on the composition, metabolism, differentiation, and characteristics of opsin expression in retina photoreceptors. METHODS: Cultures of rat retinal neurons were incubated with or without 22:6 n-3, 22:5 n-3, 20:4 n-6, 18:1 n-9, and 16:0, labeled and unlabeled. RESULTS: In photoreceptor cells incubated with 22:6 n-3 and 22:5 n-3, the proportions of these fatty acids in phospholipids increased four- to sixfold. The remaining fatty acids did not change lipid acyl chain composition. The labeled fatty acids were all actively esterified in neuronal lipids, particularly in phosphatidylcholine. Addition of unlabeled 22:6 n-3 did not affect the distribution among lipids of the other fatty acids but displaced [3H]20:4 n-6 from phosphatidylcholine and phosphatidylethanolamine. These results suggest that retinal neurons have specific mechanisms for processing fatty acids of different lengths and degrees of unsaturation and that 22:6 n-3 incorporation takes priority. Of all fatty acids, 22:6 n-3 was the most effective in promoting photoreceptor differentiation. In 22:6-sufficient photoreceptors, new apical processes formed, the expression of opsin augmented, and its localization improved, concentrating in the apical processes of the cells. CONCLUSIONS: The advancement in differentiation selectively elicited by 22:6 correlates with the fact that 22:6 n-3, but none of the other fatty acids, delays significantly the onset of apoptosis in photoreceptors in culture. The synthesis of 22:6-containing phospholipid molecules could be required for the proper localization of opsin. This could contribute to furthering the differentiation of photoreceptors, preventing their apoptosis, and extending their survival.

Animals↗
PubMed2000

Differential effects of several retinoid receptor-selective ligands on squamous differentiation and apoptosis in airway epithelial cells.

The roles of the different retinoid receptors on the differentiation of rabbit tracheal epithelial (RbTE) cells in primary culture were analysed using selective agonists for the retinoid acid receptor subtypes RARalpha (CD336), RARbeta (CD2019), RARgamma (CD437), an RAR panagonist (CD367), a retinoid X receptor RXR panagonist (CD2624) and an antagonist for RARbeta/gamma (CD2665). Squamous differentiation was assessed via expression of cytokeratins CK13/CK4 and transglutaminase I (TGI), specific markers of metaplasia. Treatment with RARalpha and beta agonists or RAR panagonist, but not the RARgamma agonist or RXR agonist, is required for the inhibition of squamous metaplasia, evidenced by inhibition of CK13/CK4 and TGI expression. The expression of CK10 cytokeratin of keratinizing epithelia, CK14/CK5 basal cell cytokeratins, and CK6 marker of cell proliferation decreases upon exposure of the RARaalpha/beta and RXR agonists. The RARgamma agonist CD437, inactive in the decrease in CK13/CK4, CK10 and CK14, reduces CK5/CK6 amounts. CD437 is responsible for a dose-dependent apoptotic response. Nuclear labelling with propidium iodide (PI) and electron microscopy revealed chromatin condensation and nuclear fragmentation. DNA cleavage and cell fragmentation were confirmed by enzyme-linked immunosorbent assay (ELISA) and flow cytometry. The RARbetagamma antagonist was also slightly active. The results indicate that CD437 causes growth arrest in the early S-phase of the cell cycle and prevents the transition G1-S-phase. CD437 was demonstrated to induce apoptosis in the S-phase cells identified by bromodeoxyuridine (BrdU) incorporation. In conclusion, RARalpha/beta ligands are effective inhibitors of squamous differentiation. On the contrary, RARgamma ligand appears to be inefficient in metaplasia inhibition, but the selective RARgamma agonist CD437 induces growth arrest and apoptosis of basal proliferative cells.

Animals↗
PubMed2006

Molecular evolution of 5' flanking regions of 87 candidate genes for atherosclerotic cardiovascular disease.

Inter-individual variation in quantitative traits as well as in disease susceptibility may be due to differences in the level and spatio-temporal pattern of gene expression. An evolutionary model of genetic variation in cis-regulatory regions may help identify loci of interest for the study of the genetic basis of complex diseases such as atherosclerotic cardiovascular disease (ASCVD). We studied the molecular evolution of 87 candidate genes for ASCVD to detect signatures of selection in 5' flanking regions. Resequenced data for these genes were available in 24 African-Americans, 23 European-Americans, and 1 chimpanzee (Pan troglodytes). Statistical tests of evolutionary neutrality (Tajima's D and Fay and Wu's H) were performed using coalescent simulations under a standard neutral model and a population structure model to differentiate selection from human demographic history. Evidence suggestive of selection was present in 5' flanking regions of 15 genes. A modified McDonald-Kreitman test was used to compare the ratio of putative functional and non-functional sites between and within species in 5' flanking regions. A significant excess or deficit of fixed changes over polymorphisms was noted in 16 genes. Of the 26 genes showing deviation from evolutionary neutrality based on the above two tests, 13 genes showed an unusual haplotype pattern in 5' flanking regions, providing supportive evidence of selection. These results indicate that selection may play a role in establishing variation in 5' flanking regions of a subset of candidate genes for ASCVD and motivate further studies of these loci in determining inter-individual susceptibility to ASCVD.

5' Flanking Region↗