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PubMed1998

A multivariate quantitative-genetic analysis of behavioral development in mice.

The present experiment attempted a behavior-genetic dissection of early behavioral development in laboratory mice. To this end, we used a full, replicated diallel cross to uncover the genetical architecture as well as the multivariate genetic structure underlying early behavioral ontogeny. A number of standard sensorimotor tests were administered on postnatal Days 3, 5, 8, 10, 13, 17, and 22 to a total of 622 pups from 120 litters (4-6 pups per litter) from a four times replicated complete diallel cross between five inbred mouse strains. The first day on which an animal showed adult performance was taken as its score on that test. MANOVA did not show any effects of the pup's sex on the speed of development. Hayman's analysis of variance for diallel tables indicated no or only weak additive-genetic effects. Dominance was absent in almost all cases, except for the auricular startle response, where weak directional dominance for fast development was found. These results are in accordance with an evolutionary past of directional selection for well-canalized development. Factor analyses of the phenotypic and additive-genetic correlation matrices indicate that at least two factors are necessary to describe the behavioral variation.

Adaptation, Psychological↗
PubMed1989

Increased exercise tolerance and reduced electrocardiographic ischaemia 3 and 12 hours after oral felodipine in effort angina.

The antianginal properties and the duration of action of two doses of felodipine, a dihydropyridine calcium antagonist with a vascular:myocardial potency ratio approximating 100:1, were investigated in 15 patients suffering from disabling effort angina pectoris with reproducible exercise tolerance. Felodipine (5 mg, 10 mg) and placebo were administered once in the morning on three different days, with a 24 h interval between them, according to a double-blind 3 x 3 latin square design, 5 times replicated. Symptom-limited cycloergometric exercise tests were performed 3 and 12 h after administration. Duration of exercise to ST segment depression of 1 mm and to peak exercise was increased (all P less than 0.01) by both doses of felodipine in comparison with placebo. Twelve hours after administration, the 10-mg dose induced a significant improvement in the exercise time and a smaller ST segment depression (all P less than 0.01) in comparison with the 5-mg dose. The relationship between ST segment depression and the pressure-rate product during exercise was favourably influenced by the 10-mg dose at 3 and 12 h after intake, and by the 5-mg dose only at 3 h after intake. These findings suggest an increase in coronary blood flow induced by felodipine. Apart from mild headache there were no other unwanted effects. In conclusion, felodipine improves exercise tolerance and reduces electrocardiographic ischaemia for up to 12 h after single oral administration in patients with effort angina. Increasing the dose from 5 mg to 10 mg produces a more prolonged effect, with increased exercise tolerance 12 h after intake.

Administration, Oral↗
PubMed1993

Regional base composition variation along yeast chromosome III: evolution of chromosome primary structure.

The recent determination of the complete sequence of chromosome III from the yeast Saccharomyces cerevisiae allows, for the first time, the investigation of the long range primary structure of a eukaryotic chromosome. We have found that, against a background G+C level of about 35%, there are two regions (one in each chromosome arm) in which G+C values rise to over 50%. This effect is seen in silent sites within genes, but not in noncoding intergenic sequences. The variation in G+C content is not related to differential selection of synonymous codons, and probably reflects mutational biases. That the intergenic regions do not exhibit the same phenomenon is particularly interesting, and suggests that they are under substantial constraint. The yeast chromosome may be a model of the structure of the human genome, since there is evidence that it is also a mosaic of long regions of different base compositions, reflected in wide variation of G+C content at silent sites among genes. Two possible causes of this regional effect, replication timing, and recombination frequency, are discussed.

Animals↗
PubMed1981

Evidence of diurnal variation of human epidermal cell proliferation. II. Duration of epidermal DNA synthesis.

In the epidermis of six healthy male volunteers the DNA synthesis time was measured by in vitro double labeling technique in a longitudinal study (48 h) with taking skin punch biopsies every 6 h. The external conditions of the experiments and one group of volunteers were identical to those of a previous study on LI of the epidermal keratinocytes. 14C-thymidine and 3H-thymidine were used for double labeling the DNA-synthesizing nuclei of keratinocytes. The duration of DNA replication time proved to be nearly constant, with minor fluctuation, during the entire time span of experiments (mean 6.19 +/- 0.3 h). Thus, the present results are in accordance with the conception that a periodically changing entrance rate of G1-cells into the S-phase of the generation cycle of keratinocytes is predominantly responsible for circadian variations in the number of DNA-synthesizing epidermal keratinocytes.

Adult↗
PubMed1997

Automation-induced monitoring inefficiency: role of display location.

Operators can be poor monitors of automation if they are engaged concurrently in other tasks. However, in previous studies of this phenomenon the automated task was always presented in the periphery, away from the primary manual tasks that were centrally displayed. In this study we examined whether centrally locating an automated task would boost monitoring performance during a flight-simulation task consisting of system monitoring, tracking and fuel resource management sub-tasks. Twelve nonpilot subjects were required to perform the tracking and fuel management tasks manually while watching the automated system monitoring task for occasional failures. The automation reliability was constant at 87.5% for six subjects and variable (alternating between 87.5% and 56.25%) for the other six subjects. Each subject completed four 30 min sessions over a period of 2 days. In each automation reliability condition the automation routine was disabled for the last 20 min of the fourth session in order to simulate catastrophic automation failure (0 % reliability). Monitoring for automation failure was inefficient when automation reliability was constant but not when it varied over time, replicating previous results. Furthermore, there was no evidence of resource or speed accuracy trade-off between tasks. Thus, automation-induced failures of monitoring cannot be prevented by centrally locating the automated task.

Adolescent↗
PubMed1981

Vitamin B12-dependent replication of L1210 mouse leukemia cells. A model system for cobalamin-folate inter-relationships.

L1210 mouse leukemia cells were made cobalamin-deficient by propagation in a medium from which cyanocobalamin was omitted and fetal bovine serum (containing protein-bound cobalamins) was replaced by bovine serum albumin. These cobalamin-deficient cells exhibited a normal replication time of 12 h, provided that the medium contained excess folate or 5-formyltetrahydrofolate. The cells responded poorly, however, to 5-methyltetrahydrofolate unless exogenous cobalamin was added. A cobalamin dependency was also observed when low levels of folate or 5-formyltetrahydrofolate were used. With 5-methyltetrahydrofolate, optimal stimulation of growth was observed with free and transcobalamin-II-bound cobalamin at 4,000 pM and 2 pM, respectively. Under cobalamin-replete conditions, cells contained 2,000 to 4,000 molecules of cobalamin/cell, and in the deficient state, this value declined to less than 10 molecules/cell; optimal replication on 5-methyltetrahydrofolate required approximately 180 molecules/cell. Cobalamin-deficient cells cultured in the absence of folate reached an arrested state from which limited replication could be induced by the addition of aquacobalamin; normal replication was induced by aquacobalamin plus 5-methyltetrahydrofolate. Results of this investigation are interpreted in terms of the requirement for tetrahydrofolate in cell replication and the production of this compound from folate and 5-formyltetrahydrofolate (via cobalamin-independent pathways) and from 5-methyltetrahydrofolate (via the cobalamin-dependent methionine synthetase).

Animals↗
PubMedDate not supplied

C-myc transcript is induced in rat liver at a very early stage of regeneration or by cycloheximide treatment.

In rats, partial hepatectomy induces reasonably synchronized DNA replication in the remaining liver after approximately 20 h. Events occurring during the earlier stages of liver regeneration are of interest because they may tell us how cells in vivo respond when they move from a differentiated resting state (G0 phase) to a proliferative state. We report here that the expression of the c-myc oncogene is increased up to 10-15-fold of the normal level within 1-3 h after partial hepatectomy. This expression begins to decrease rapidly after 4 h and has returned to less than double the normal level after 8 h, at which time replicative DNA synthesis has still not begun. A still larger increase in c-myc transcription (approximately 600-fold) is observed in the liver when protein synthesis is inhibited by an injection of cycloheximide. These findings suggest the existence of a short-lived protein that is synthesized soon after partial hepatectomy, and which suppresses the expression of c-myc.

Animals↗
PubMed1993

Immunoglobulin heavy chain enhancer is located near or in an initiation zone of chromosomal DNA replication.

In several animal viruses, enhancers have been implicated in both DNA replication and transcriptional activation. The linkage of the two mechanisms appears intimate, in that common DNA binding factors can be shared. The immunoglobulin heavy chain (Igh) intronic [heavy chain joining region (JH)-mu chain constant region (C mu)] enhancer (E mu) is required for tissue-specific transcription of Igh genes and is essential for somatic recombination of diversity (D) and J segments. We show here that E mu is located at or near an origin of chromosomal DNA replication, which is more active in B lymphocytes than fibroblasts. E mu does not fulfill two criteria demonstrated for some cellular origins. E mu can initiate but not maintain autonomous replicating activity in B cells. E mu is unable to impart early replication timing to a transfected VDJ-C mu Igh locus in B cells. Instead we propose that E mu-associated ori activity contributes to tissue-specific Igh expression through local effects on chromatin structure leading to subsequent accessibility of transcription and/or recombination factors for the enhancer.

3T3 Cells↗
PubMed2000

Replication asynchrony increases in women at risk for aneuploid offspring.

We attempted to demonstrate a relation between a loss of replication control, centromere dysfunction, and predisposition to non-disjunction. Couples with a Down syndrome offspring were the high-risk probands. One-color FISH (fluorescent in-situ hybridization) was applied to interphase nuclei (lymphocytes). Replication pattern of two pairs of alleles, RB-1 and 21q22, were studied, and the rate of aneuploidy was estimated using two alpha-satellite probes of chromosomes 8 and 18. Our results suggest the existence of an association between replication timing and the rate of non-disjunction. A higher rate of allele asynchrony and aneuploidy was found in older women and in mothers of a Down syndrome offspring. These findings may reflect a predisposition for meiotic non-disjunction in these women.

Adult↗
PubMed1996

Kinetics of duck hepatitis B virus infection following low dose virus inoculation: one virus DNA genome is infectious in neonatal ducks.

Using pooled serum from congenitally duck hepatitis B virus (DHBV)-infected ducks as inoculum, we examined the effect of virus dose on the incubation period of infection and on the patterns of spread of virus infection in the liver. The pooled serum inoculum contained 9.5 x 10(9) DHBV genomes per milliliter and had an infectivity titre (ID50) in newly hatched ducks of 1.5 x 10(10) per milliliter with a 95% confidence interval of 3.0 x 10(9) to 6.3 x 10(10) ID50/ml, indicating the equivalence between one DHBV genome and one infectious unit within the limits of the assays. The incubation period of infection was inversely related to the dose of inoculum and the onset of viraemia ranged from Day 6 with the highest dose to Day 14 or 29 with the lowest dose inoculum. To study the spread of virus infection from a low percentage of initially infected cells we inoculated newly hatched ducks intravenously with sufficient DHBV (1.5 x 10(3) ID50) to infect only approximately 0.0001% of total liver cells. DHBV infection first reached detectable levels on Day 4 postinoculation (p.i.) and was detected in approximately 0.035% of hepatocytes, most of which occurred as single cells or pairs of cells, indicating that a number of rounds of infection had occurred with the spread of virus both to adjoining cells, i.e., by cell-to-cell spread, and to cells located in other parts of the liver lobule. Despite some bird-to-bird variation in timing, the percentage of infected hepatocytes increased exponentially with a mean doubling time of 16 hr from Day 4 to Day 14 p.i., by which time replication was seen in > 95% of hepatocytes. This rapid dissemination from a small number of infected hepatocytes suggests that, in neonatal ducks, there are no major delays in virus replication within the liver, that any innate and adaptive defence mechanisms operating during the first 10 to 14 days of infection are insufficient to contain virus spread, and that even a small number of infected hepatocytes produce enough progeny to rapidly infect the remaining hepatocytes.

Age Factors↗
PubMed1998

Determining the optimal thymidine concentration for growing Thy- Escherichia coli strains.

Changes of thymidine concentration in the growth medium affect the chromosome replication time of Thy- strains without at the same time causing a detectable difference in the growth rate (R. H. Pritchard and A. Zaritsky, Nature 226:126-131, 1970). Consequently, the optimal thymidine concentration cannot be determined by ascertaining which concentration produces the highest growth rate. Here we present a method for determining the optimal thymidine concentration of any Thy- Escherichia coli strain. Using this method, we found that the E. coli "wild-type" strain MG1655 has a partial Thy- phenotype.

Bacteriological Techniques↗
PubMed1997

Replication initiation and elongation fork rates within a differentially expressed human multicopy locus in early S phase.

Replication of the 400 copies of the 43 kb human ribosomal RNA (rDNA) locus spans most of the S phase. To examine the basis for the unusual pattern of rDNA replication, a sensitive strategy was developed to map origins of DNA replication and measure apparent rates of fork progression within a chromosomal locus. This technique, termed differential intragenomic replication timing, revealed that initiation within the actively transcribed rDNA occurred in early S within a 10.7 kb region spanning the promoter and 5' external transcribed spacer. Forks emanating from this early bidirectional origin progressed at an apparent slow rate with the sense and anti-sense forks moving at 0.32 and 0.23 kb/min. Using a photochemical-based technique, the chromatin status of the rDNA repeats was assayed throughout the S phase. Approximately 85% of the rDNA repeats were in a transcriptionally active chromatin structure at the start of S phase. A progressive decrease in the transcription state of the rDNA loci was observed, reaching a minimum between 3 and 6 h in mid S phase. Altogether, the data suggest a link between RNA polymerase I mediated transcription and site-specific initiation of DNA replication within the rDNA multicopy locus.

Chromatin↗
PubMed1990

DNA methylation and late replication probably aid cell memory, and type I DNA reeling could aid chromosome folding and enhancer function.

DNA methylation in mammals is reviewed, and it is concluded that one role of methylation is to aid cell memory, which is defined as the ability of mitotically derived progeny cells to remember and re-establish their proper cellular identity. Methylation of X-linked CpG-rich islands probably stabilizes X-chromosome inactivation, but other mechanisms appear to be involved. Late replication is discussed as a key ancestral mechanism for X inactivation, and it is emphasized that early and late replication domains may each be self perpetuating. Therefore, early-late replication timing becomes another strong candidate mechanism for cell memory. A chromosome-loop folding enigma is discussed, and it is concluded that special mechanisms are needed to explain the formation and maintenance of specific looped domains. DNA reeling, such as done by type I restriction-modification enzymes, is proposed to provide this special mechanism for folding. DNA reeling mechanisms can help to explain the cis-spreading of X-chromosome inactivation as well as long-range action by enhancers.

Animals↗
PubMed1999

Abnormal methylation does not prevent X inactivation in ICF patients.

DNA undermethylation is a characteristic feature of ICF syndrome and has been implicated in the formation of the juxtacentromeric chromosomal abnormalities of this rare syndrome. We have previously shown that in female ICF patients the inactive X chromosome (Xi) is also undermethylated. This result was unexpected since female ICF patients are not more severely affected than male patients. Here we show that CpG island methylation is abnormal in some ICF patients but in other ICF patients, the difference in methylation pattern between Xi and Xa (active X) is maintained. The consequences of Xi undermethylation on gene expression were investigated by enzyme assays. They showed that significant gene expression did not correlate with CpG island methylation status. The widespread Xi undermethylation does not affect overall Xi replication timing and does not prevent Barr body formation suggesting that a normal methylation pattern is not required for normal chromatin organization of Xi. Molecular investigation of some X-chromosome intron regions showed that the methylation changes in ICF female patients extend to non CpG islands sequences. Our results suggest that the genetic alteration of DNA methylation in ICF syndrome has little consequence on X chromosome gene expression and chromatin organization.

Centromere↗
PubMed1995

[In situ quantitative analysis of Drosophila histone gene in S-phase].

We used a novel multiparametric microfluorometry analytic system to determine the replication timing of Drosophila histone gene DNA by in situ quantitative analysis of the gene in S-phase under a fluorescent microscope. There are 110 copies of histone genes per genome and each one of them is 5 kb in size. Primary cultured embryo cells were used to make preparations for microscopic analysis. Cells were first stained with DAPI and the total nuclear DNA contents in each nucleus reflected on the fluorescent intensity. We collected data of the fluorescent intensity from 400 of the cells in S-phase (Fig. 4). Then, the very same preparation was subjected to FISH (fluorescent in situ hybridization) using biotinylated DNA probes and FITC, and the fluorescent intensity of the hybridization signals were quantitatively detected from the same 400 cells and in the same order. This data showed the relative quantity of the signals representing the histone genes. From the correlation of fluorescent intensity of DAPI and that of FITC of the cells in S-phase, we found that the histone gene DNA completed its replication during early stage in S-phase (Fig. 5). The method we introduced here is considered to be able to use in many other cases of quantitative analysis directly in cells.

Animals↗
PubMed2001

Marek's disease virus infection in the brain: virus replication, cellular infiltration, and major histocompatibility complex antigen expression.

Marek's disease virus (MDV) infection in the brain was studied chronologically after inoculating 3-week-old chickens of two genetic lines with two strains of serotype I MDV representing two pathotypes (v and vv+). Viral replication in the brain was strongly associated with the development of lesions. Three viral antigens (pp38, gB, and meq) were detected in the brain of infected chickens. Marked differences between v and vv+ pathotypes of MDV were identified for level of virus replication, time course of brain lesions, and expression of major histocompatibility complex (MHC) antigens. Two pathologic phenomena (inflammatory and proliferative) were detected in the brain of chickens inoculated with vv+MDV, but only inflammatory lesions were observed in those inoculated with vMDV. Inflammatory lesions, mainly composed of macrophages, CD4+ T cells, and CD8+ T cells, started at 6-10 days postinoculation (dpi) and were transient. Proliferative lesions, characterized by severe infiltrates of CD4+CD8- T cells (blasts), started at 19-26 dpi and persisted. Expression of MHC antigens in endothelial cells and infiltrating cells within the brain was influenced by MDV infection. Upregulation of MHC class II antigen occurred in all treatment groups, although it was more severe in those inoculated with vv+MDV. MHC class I antigen was downregulated only in those groups inoculated with vv+MDV. These results enhance our understanding of the nature and pattern of MDV infection in the brain and help to explain the neurovirulence associated with highly virulent MDV.

Animals↗
PubMed1995

Induction of feline acquired immune deficiency syndrome by feline leukemia virus: alteration in response to hormones in the hypothalamic-pituitary-gonadal system.

Male kittens who were infected with the feline leukemia virus (FeLV) were found at various times after exposure to contain a sequence of dysfunction in their hypothalamic-pituitary-gonadal (HPG) system. To understand whether the involved endocrine glands in this system were damaged by FeLV, the hypothalamus, pituitary, and testes were tested for hormonal responsiveness in vivo and in vitro. The infected cats were administered with luteinizing hormone-releasing hormone (LHRH) and human chorionic gonadotropin (hCG). Their response to the treatment was studied, and they were then compared with untreated control cats. Normal response to LHRH for the synthesis of follicle stimulating hormone (FSH), luteinizing hormone (LH), and testosterone were found in the infected cats prior to 10 weeks of infection. After 10 weeks, the response was reduced by 25%, 38%, and 42%, respectively. Twelve weeks after infection, the response to hCG for testosterone synthesis was drastically reduced. The control cats, however, demonstrated normal prolonged biphasic patterns of response to hCG. The in vivo administration of the tropic hormones had no effect on the titer of FeLV gs antigen in the blood of the infected cats. The medial basal hypothalamus (MBH) from the control cats and cats in their 13th week of infection were cultured in vitro, with the presence of high K+ ion (60 mM). The control MBH responded to K+ ion stimulation for LHRH release. The K(+)-stimulated release of LHRH in the control MBH was 99% higher than that of the infected MBH. In contrast, the amount of unreleased LHRH in the infected MBH was 74% higher than that of the control MBH. In in vitro culture, the control pituitary gland responded markedly higher to LHRH stimulation for the release of gonadotropins (FHS and LH) than that of the infected one (140% compared with 56% for FSH, and 70% compared with 28% for LH, respectively). Whereas, the amount of unreleased FSH and LH in the infected pituitary gland were 59% and 31%, higher than that of the control gland. These results suggest that (i) the progressive development of neuroendocrine glands' dysfunction is related to viral replication time; (ii) the in vivo and in vitro responses to tropic hormones in the infected endocrine glands are drastically reduced; and (iii) this reduction in hormonal response may be caused by defective regulation of peptide hormonal secretion.

Animals↗
PubMed1988

Relationship between the timing of DNA replication and the developmental competence in Acanthamoeba castellanii.

In Acanthamoeba, two different cell types are known. Trophozoites are generated in the mitotic division cycle, whereas cells committed at late G2 phase of the cell cycle develop into cysts in response to starvation. In this paper we study the role of timing of DNA replication in regulating development. The investigation was performed with cultures growing in a non-defined medium (ND cells) that show a high encystation competence and with cultures that have been growing in a chemically defined medium (D cells) for several years and show a low encystation competence. Bivariate DNA/BrdUrd distributions show that ND cells progress through a cycle in which the short replication phase occurs immediately and exclusively after prior completion of mitosis. These cells arrest at late G2 phase of the cell cycle during the stationary stage. In D cells, DNA replication and mitosis seem to be uncoupled, since replication takes place before as well as after mitosis. These cells arrest within their replication phase during the stationary stage. These findings indicate that D cells do not progress into late G2 phase of the cell cycle and hence do not have the competence for commitment. The alternate timing of DNA replication and the low encystation competence of D cells can be reversed by cultivation of these cells in ND medium. Synchronization experiments reveal that late G2 phase ND cells exhibit a low capacity for BrdUrd incorporation and growth after transfer into D medium, whereas ND cells of earlier phases of the cell cycle show premitotic incorporation of BrdUrd into nuclear DNA and growth. These findings suggest on the one hand that premitotic DNA synthesis is a prerequisite for growth of cells in D medium, and that there is a dependence of the induction of premitotic DNA synthesis on the cell cycle, and on the other hand that a reciprocal relationship exists between the capacity of premitotic DNA synthesis and commitment to differentiation.

Acanthamoeba↗