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Results for “Replication Timing”

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At least 127 records · Page 7Linked to original sources
PubMed1984

[Morphologic criteria of the growth behavior of pancreatic cancers. Experimental and clinico-pathologic studies].

In order to improve the individual characterization of ductal adenocarcinoma of the pancreas histologic and cytologic criteria of tumour differentiation were correlated with tumour growth. The most relevant parameters of grading were glandular differentiation, nuclear polymorphism and frequency of mitoses (number of mitoses per ten visual fields with magnification through the 40 objective). Using these criteria three grades of tumour (G) were separated. In 7 human adenocarcinomas of the pancreas transplanted onto nude mice GIII tumours showed a tumour replication time of approximately half of that of GI tumours. In an additional clinico-pathological study in 75 partial or total pancreas resection preparations with carcinoma of the head of the pancreas a significantly longer symptomatic time until diagnosis was found in GI tumours (n = 34) than in GII (n = 33) and GIII tumours (n = 8). Besides, GI tumours showed a generally lower staging at the time of operation than did GII and GIII tumours. The median values of postoperative survival time for GI (n = 12) and GII tumours (n = 12) with identical staging was 10.5 and 7 months, respectively. The results indicate that the suggested grading of ductal adenocarcinomas of the pancreas reflects the biological behaviour of these tumours and can thus be used as an additional prognostic parameter in staging.

Adult↗
PubMed2026

Genetic control of local mutation rates.

Mutations are the source of evolutionary novelty but also the cause of genetic diseases and cancer. Mutation rates are known to be heterogeneous along the genome, however the extent to which local mutation rates vary among individuals in a population and are genetically determined is unknown. To test this, we analyzed the chromosomal distribution of somatic mutations in cell lines from 1,662 individuals, controlling for the confounding effects of DNA replication timing on local mutation rates and of trans-acting modulators on global mutation rates. We describe substantial interindividual variation in mutation rates across the human genome. By comparing mutation-rate variation to individuals' genotypes, we identified 35 instances in which polymorphic alleles in the population associate with somatic mutation rates in their vicinity. We call these mutation quantitative trait loci (mutQTLs). mutQTLs associated with somatic mutations in lymphoblastoid cell lines and in chronic lymphocytic leukemia, and with germline genetic variants. Two of the four mutQTLs inferred to be associated with germline mutation-rate variation were located within large clusters of zinc-finger genes and transposable elements, where they functioned as cis-mutators conferring an increased rate of mutation in their vicinity. mutQTLs provide a portal into the evolution of mutation rate heterogeneity across the genome and across individuals.

Humans↗
PubMed1992

Activation of the beta-globin locus control region precedes commitment to the erythroid lineage.

The beta-globin locus control region (LCR) is characterized by erythroid-specific DNase I hypersensitive sites and is involved in the chromatin organization, transcriptional potentiation, developmental regulation, and replication timing of the entire beta-globin gene cluster. When and how the LCR is first activated during erythropoiesis is not known. Here we analyze the chromatin structure of the LCR during early hematopoietic differentiation using nontransformed, multipotential, growth factor-dependent, murine hematopoietic progenitor cells. We show that LCR hypersensitive sites characteristic of erythroid cells are present in three independent multilineage progenitors [FDCP (factor-dependent cell, Paterson)-mix A4, B6SUtA, and LyD9] under conditions of self-renewal. Induction of differentiation down a nonerythroid pathway causes a progressive loss of hypersensitivity in the LCR. These results show that the beta-globin LCR is in an active chromatin configuration prior to erythroid commitment and indicate a significant role for selective gene repression in lineage specification.

Animals↗
PubMed2025

CDACHIE: chromatin domain annotation by integrating chromatin interaction and epigenomic data with contrastive learning.

MOTIVATION: Chromatin domain annotation identifies functional genomic regions, such as active and inactive zones, based on epigenomic features like histone modifications, DNA methylation, and chromatin accessibility. While recent methods have utilized both chromatin interaction data (e.g. Hi-C) and epigenomic data, they often overlook the direct relationship between these data types. RESULTS: In this study, we introduce Chromatin Domain Annotation using Contrastive Learning for Hi-C and Epigenomic Data (CDACHIE), a method for identifying chromatin domains from Hi-C and epigenomic data. Our approach leverages contrastive learning to generate aligned representative vectors for both data types at each genomic bin. The concatenated vectors are then clustered using K-means to classify distinct chromatin domain types. CDACHIE achieves superior performance in Variance Explained, evaluated across gene expression, replication timing, and ChIA-PET data. This highlights its robust ability to integrate semantic associations between Hi-C and epigenomic features within the embedding space. AVAILABILITY AND IMPLEMENTATION: The source code is available at GitHub: https://github.com/maruyama-lab-design/CDACHIE. An archival snapshot of the code used in this study is available on Zenodo: https://doi.org/10.5281/zenodo.15751780.

Chromatin↗
PubMed1987

A rapid method for the evaluation of new antituberculous agents.

Fifty-one new synthetic compounds belonging to four different series, namely (1a) substituted aryl-4-(substituted phenyl) succinimide; (1b) N-(substituted methyl)-4-(heterocyclic) succinimide; (2) heterocyclic 4-(5'-nitro-2-furyl) thiazoles; (3) substituted aryl-4-(3', 4'-dihydroxy phenyl) thiazoles, and (4) phenyl-N,N-1,2,3-bis-methoxy carbonyl guanidines were screened for antituberculous activity using a conventional broth dilution test (BDT) and a liquid scintillation radiometric method (LSRM). Eight compounds showed in vitro activity. LSRM showed 100% agreement with BDT. LSRM is completed within 60 h, while BDT requires 8-9 days. Unlike BDT, LSRM allowed one to measure the graded changes in the metabolism and the growth rate of Mycobacterium tuberculosis in response to various concentrations of the drug. It permits the measurement of the relative prolongation of the replication time by the drug or the test compound. With LSRM it was possible to detect the phase of growth during which the test compound shows or begins its antituberculous activity. It improves our understanding of the antituberculous activity of the test compound and hence is more advantageous. It is rapid, reliable, quantitative and more sensitive than BDT. LSRM is thus suitable for the evaluation of new drugs.

Antitubercular Agents↗
PubMed1987

Neurologic abnormalities and recovery of human immunodeficiency virus from cerebrospinal fluid.

Infectious human immunodeficiency virus (HIV) was recovered from 30 of 48 cerebrospinal fluid specimens from seropositive persons with and without neurologic symptoms or disease. Of 16 patients with only neurologic problems or other HIV-related conditions, but not the acquired immunodeficiency syndrome (AIDS), 11 had virus recovered; over half of those with AIDS also had virus isolated. Patients with headache or altered mental status had the highest recovery rate of HIV from cerebrospinal fluid. Although virus was primarily found in patients with detectable neurologic disease, it was also isolated from 5 of 8 patients with normal neurologic examinations. Two of these patients had fever alone. The presence of virus in cerebrospinal fluid did not necessarily correlate with isolation of virus from the serum. These findings suggest that HIV may at times replicate preferentially in the brain and that its presence may not immediately cause neurologic signs or symptoms.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Diallel genetic analysis of the elements of paradise fish's (Macropodus opercularis L.) behavior in familiar and novel situations.

Elements of the paradise fish's ethogram were recorded in 1 familiar and 3 different unfamiliar situations and the inheritance of these behavioral elements was investigated employing a five times replicated diallel cross between 3 inbred strains. A generalized Hayman Analysis of Variance and a Variance Covariance Analysis were performed to estimate genetic effects and parameters, such as, additive genetic variance, different sorts of dominance variance, reciprocal effects, direction and degree of dominance, ratio between the frequency of dominant and of recessive alleles, minimum number of effective factors and heritabilities, etc. Knowing the genetic architecture, we make inferences about the possible evolutionary past of the behavioral elements and explain why selection might favor certain types of paradise fish's behavior in particular circumstances. In several cases a possibility of "monogenic" inheritance emerged. We explain this finding and conclude that in a cross experiment where the inheritance of phenotypical units are investigated by employing only a few genetically different strains this result may be expected.

Alleles↗
PubMed1988

The aortic intima in organ culture. Response to culture conditions and partial endothelial denudation.

A culture technique for whole blood vessel wall that preserves an intact and regenerative endothelium has been developed. The retention of an intact endothelium allows careful observation of the tissue as it responds to culture conditions, responses that include a change of replication timing and the induction of particulate endocytosis. Complete and normal regeneration of the endothelium in explants has made possible evaluation of the differences between the regeneration of endothelial cell monolayers and regeneration of intima in vivo. From these comparisons it appears that the shorter induction time of endothelial migration and proliferation and the more rapid migration in endothelial cell monolayers are due to effects of the culture medium or plastic culture surface, while the higher than normal cell density found in the intima after wound recovery in vivo probably is due to the dynamics of the blood vessel itself. The ability to control cell-cell interactions on the cultured tissue has made possible the investigation of gap junction-mediated metabolic interactions in regenerating intima. Results indicate that the disruptive effects of intimal regeneration do not depend on or produce an obvious change in junction-mediated nucleotide transfer between endothelial cells.

Animals↗
PubMed1985

Nitroderm TTS in exercise-induced angina pectoris--a randomized double-blind study.

Nitroderm TTS is a new transdermal delivery system for nitroglycerin, consisting of a self adhesive disc from which the drug diffuses into the skin at a predetermined rate through a microporous membrane. In an acute, randomized, double-blind, within-patient study, a TTS formulation releasing 10 mg of nitroglycerin over 24 hours (TTS 10) was compared with placebo and isosorbide dinitrate (ISDN) 20 mg slow-release. TTS 10, ISDN and placebo were given on 3 successive days, according to a 3 X 3 latin square design 3 times replicated, to 9 in-patients with coronary heart disease and stable exercise-induced angina pectoris. At rest, both TTS 10 and ISDN significantly lowered lying (p less than 0.05) and standing (p less than 0.01) systolic blood pressure as compared to placebo, but there was no difference between the 2 active treatments. On the symptoms-limited cycloergometric exercise test, carried out 4 hours post-dosing, both TTS 10 and ISDN significantly (p less than 0.05) improved exercise tolerance in respect to placebo. Treatments were well tolerated. In conclusion, both TTS 10 and ISDN, 4 hours post-dosing, are superior to placebo in improving exercise tolerance in patients with coronary heart disease and exercise-induced angina pectoris. The transdermal therapeutic system, allowing constant plasma nitroglycerin levels over 24 hours, has the advantage of once daily administration.

Adult↗
PubMed1983

ARS replication during the yeast S phase.

A 1.45 kb circular plasmid derived from yeast chromosome IV contains the autonomous replication element called ARS1. Isotope density transfer experiments show that each plasmid molecule replicates once each S phase, with initiation depending on two genetically defined steps required for nuclear DNA replication. A density transfer experiment with synchronized cells demonstrates that the ARS1 plasmid population replicates early in the S phase. The sequences adjacent to ARS1 on chromosome IV also initiate replication early, suggesting that the ARS1 plasmid contains information which determines its time of replication. The times of replication for two other yeast chromosome sequences, ARS2 and a sequence referred to as 1OZ, indicate that the temporal order of replication is ARS1 leads to ARS2 leads to 1OZ. These experiments show directly that specific chromosome regions replicate at specific times during the yeast S phase. If ARS elements are origins of chromosome replication, then the experiment reveals times of activation for two origins.

DNA Replication↗
PubMed1989

Activation and repression of a beta-globin gene in cell hybrids is accompanied by a shift in its temporal replication.

To investigate whether a switch in the transcriptional activity of a gene is associated with a change in the timing of replication during the S phase, we examined the replication timing of the beta-globin genes in two different types of somatic cell hybrids. In mouse hepatoma (Hepa 1a) x mouse erythroleukemia (MEL) hybrid cells, the beta-globin gene from the MEL parent is transcriptionally inactivated and is later replicating than in the parental MEL cell line. In human fibroblast (GM3552) x MEL hybrid cells, the human beta-globin gene is transcriptionally activated, and all of the sequences within the human beta-globin domain (200 kilobases) we have examined appear to be earlier replicating than those in the parental fibroblast cell line. The chromatin configuration of the activated human beta-globin domain in the hybrids is relatively more sensitive to nucleases than that in the fibroblasts. Furthermore, major nuclease-hypersensitive sites that were absent in the chromatin flanking the distal 5' region of the human beta-globin gene cluster in the parental fibroblast cell line are present in the transcriptionally activated domain in the hybrid cell line. These results suggest that timing of replication of globin genes has been altered in these hybrid cells and thus is not fixed during the process of differentiation.

Animals↗
PubMed1988

Timing of chromosomal replication in Escherichia coli.

We have previously shown that certain mutations in the dnaA and recA genes of Escherichia coli perturb initiation of chromosomal replication so that all origins present are not initiated simultaneously. In this work, several genes whose protein products are involved in initiation of replication have been investigated for their effects on the synchrony of initiation. Some of the mutants (dnaC2, rpoC907, dam3) were found to have the asynchrony phenotype. Also, dnaA(Ts) mutations were shown to be dominant over dnaA+ in terms of initiation synchrony. The mechanism leading to the asynchronous phenotype is discussed.

Bacterial Proteins↗