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PubMed1981

The initiation of chromosome replication in a dnaAts46 and a dnaA+ strain at various temperatures.

The regulation of chromosome replication initiation was studied at various temperatures with an E. coli dnaA46 strain and its dnaA+ parent. We find that, in both strains, the "initiation mass" varies depending upon growth temperature while the replication time remains constant relative to the cell doubling time. In the permissive temperature range, the initiation mass of the dnaA46 mutant strain is larger by a constant factor than that for a dnaA+ strain. We conclude that, even at temperatures permissive for growth of the dnaA46 strain, the activity of the dnaA46 product is lower than that of the wild-type protein. The dnaA gene product, therefore, plays an important role in regulating initiation.

DNA Replication↗
PubMed2002

Asynchronous replication of alleles in genomes carrying a microdeletion.

BACKGROUND: While most allelic pairs of DNA replicate synchronously during the S phase of the cell cycle, some genes normally replicate asynchronously, i.e., genes on the X chromosome and imprinted genes. The replication control mechanism is unknown but was shown to be impaired in malignancies and chromosomal trisomies where replication pattern becomes asynchronous. OBJECTIVES: To determine the level of asynchronization in replication timing of cells from patients with microdeleted genomes. METHODS: We applied monocolor fluorescent in situ hybridization with different probes on leukocytes from microdeleted genomes. RESULTS: All samples derived from the microdeleted genomes showed significantly higher levels of an asynchronized pattern compared to normal individuals. CONCLUSIONS: Even a "small" genetic imbalance (microdeletion) can interfere with gene replication and cell cycle progression, as previously shown in full trisomies.

Allelic Imbalance↗
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↗
PubMed2005

An isochore transition zone in the NF1 gene region is a conserved landmark of chromosome structure and function.

The mammalian genome is organized as a mosaic of isochores, stretches of DNA with a distinct sequence composition. Isochores form the basis of the chromosomal banding pattern, which is tightly correlated with a number of structural and functional features. We have recently demonstrated that the transition from a GC-poor isochore to a GC-rich one in the NF1 gene region occurs within 5 kb and demarcates genomic regions with high and low recombination frequency. We now report that the same transition zone separates early replicating from late replicating chromatin on the molecular level. At the isochore transition the replication fork is stalled in mid-S phase and can be visualized by fiber-FISH techniques as a Y-shaped structure. The switch in GC content and in replication timing is conserved between human and mouse, emphasizing the importance of the transition zones as landmarks of chromosome organization and function.

Animals↗
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↗
PubMed2002

c-Myc initiates illegitimate replication of the ribonucleotide reductase R2 gene.

The mechanisms through which the oncoprotein c-Myc initiates locus-specific gene amplification are not understood. When analysing the initiation mechanism of c-Myc-dependent amplification of the mouse ribonucleotide reductase R2 (R2) gene, we observe c-Myc-dependent initiation of illegitimate DNA replication of the R2 gene. We demonstrate multiple simultaneous c-Myc-induced R2 replication forks, whereas R2 normally replicates with a single fork. In contrast, cyclin C replicates with only a single replication fork irrespective of c-Myc deregulation. In addition to de novo replication forks, c-Myc also initiates bi-allelic replication of R2, abrogating its normal mono-allelic replication pattern. Moreover, several chromosomal regions also display c-Myc-induced illegitimate replication profiles. Thus, c-Myc can act as an illegitimate replication-licensing factor that promotes de novo replication initiation and illegitimate replication timing that adversely impacts upon genomic stability.

Alleles↗
PubMed2003

The genome of bacteriophage phiKMV, a T7-like virus infecting Pseudomonas aeruginosa.

The complete DNA sequence of a new lytic T7-like bacteriophage phiKMV is presented. It is the first genome sequence of a member of the Podoviridae that infects Pseudomonas aeruginosa. The linear G + C-rich (62.3%) double-stranded DNA genome of 42,519 bp has direct terminal repeats of 414 bp and contains 48 open reading frames that are all transcribed from the same strand. Despite absence of homology at the DNA level, 11 of the 48 phiKMV-encoded putative proteins show sequence similarity to known T7-type phage proteins. Eighteen open reading frame products have been assigned, including an RNA polymerase, proteins involved in DNA replication, as well as structural, phage maturation, and lysis proteins. Surprisingly, the major capsid protein completely lacks sequence homology to any known protein. Also, the strong virulence toward many clinical P. aeruginosa isolates and a short replication time make phiKMV attractive for phage therapy or a potential source for antimicrobial proteins.

Amino Acid Sequence↗
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↗
PubMed2003

Endocrine, blood metabolite, and meat quality changes in goats as influenced by short-term, preslaughter stress.

The purpose of this study was to determine the effects of short-term, preslaughter stress on physiological responses and meat quality in goats of different age groups. The goats (n = 28) were classified into young (6 to 12 mo of age) and old (24 to 30 mo of age) groups, feed deprived overnight, and slaughtered at three different times (replicates). On each slaughter day, goats were either subjected to a 2-h transportation stressor (TS) or remained unstressed in holding pens (NS) before slaughter. Blood samples were collected via jugular venipuncture from TS and NS goats at 2, 1, and 0 h before slaughter. Muscle glycogen and pH were measured on samples from longissimus muscle (LM) collected at 15 min and 24 h postmortem, and instrumental measures of meat color were obtained on the LM after a 24-h chilling period at 4 degrees C. The TS goats had higher plasma cortisol (P < 0.01) and glucose (P < 0.05) concentrations than NS goats. The rates of increase in plasma cortisol, glucose, and nonesterified fatty acid concentrations were greater in TS than in NS goats (stressor treatment x blood sampling time, P < 0.01). Muscle glycogen concentrations were greater (P < 0.05) in NS than in TS goats and higher (P < 0.01) in old vs. young goats; however, pH measured at 15 min and 24 h postmortem was not (P > 0.05) influenced by stressor treatment. Water-holding capacity of meat was not (P > 0.05) influenced by stressor treatment. Older goats had lower (P < 0.01) L* values and greater (P < 0.01) a* and chroma values than the younger goats. The a* and chroma values of loin cuts from young goat carcasses were lower in the TS than NS treatment groups, but this effect was absent in the old goat carcasses (stressor treatment x age, P < 0.05). Cooking loss percentages and shear force values for loin chops aged for 7 d were not (P < 0.05) affected by stressor treatment; however, old goats produced tougher (P < 0.01) loin chops than young goats. These results indicate that short-term preslaughter transport can cause noticeable changes in stress responses and muscle metabolism in goats.

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↗