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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↗
PubMed1990

Characterization of the heterochromatin in moose (Alces alces) chromosomes.

The karyotype of moose (2n = 68) is characterized by very large C-bands close to the centromeres of most chromosomes. The C-banded material represents 40% of the genome. For further characterization of the heterochromatin chromosome spreads were treated with restriction endonucleases and the restriction enzyme (Re) banding pattern was analyzed. HaeIII, AluI, MboI, RsaI and HinfI produced informative Re-bands. DdeI induced an even digestion with no banding. Staining with chromomycin A3 produced bright fluorescence in regions corresponding to C-bands. Labeling with BrdUrd during late S phase differentiates four regions in the C banded area. The sequence of these regions from centromere to telomere are: late, early, late and early replicating. The authors propose the existence of five satellite DNA families with distinctive characteristics of G-C and A-Trichness and different replication timing, and point out the different clusters for the endonucleases detailed above and their varying location in the chromosomes examined.

Animals↗
PubMed1990

High-resolution dynamic and morphological G-bandings (GBG and GTG): a comparative study.

A high-resolution replication banding technique, dynamic GBG banding (G-bands after 5'-bromodeoxyuridine [BrdUrd] and Giemsa), showed that, at a resolution of 850 bands/genome, GBG banding and GTG banding (G-bands after trypsin and Giemsa) produce almost identical patterns. RBG band (R-bands after BrdUrd and Giemsa) and RHG band (R-bands after heat denaturation and Giemsa) patterns were previously shown to be only 75%-85% coincident; thus GTG banding more accurately reflects replication patterns than does RHG banding. BrdUrd synchronization uses high concentrations of BrdUrd both to substitute early replicating DNA and to arrest cells before the late bands replicate. Release from the block is via a low thymidine concentration. The banding is revealed by the fluorochrome-photolysis-Giemsa (FPG) technique and produces the GBG banding that includes concomitant staining of constitutive heterochromatin. As opposed to other replication G-banding procedures, BrdUrd synchronization and GBG banding produces a reproducible replication band pattern. The discordance between homologs after GBG banding is similar to that after GTG banding and no lateral asymmetry of the constitutive heterochromatin has been observed. Also, BrdUrd synchronization neither significantly depresses the mitotic index, nor induces chromosome breaks. Thus, GBG banding seems as clinically useful as GTG banding and provides important information regarding replication time.

Adult↗
PubMed1989

Ambulatory blood pressure monitoring during sustained treatment with conventional and extended-release felodipine in mild-to-moderate hypertension.

To assess the duration of the antihypertensive effect of the dihydropiridine calcium antagonist felodipine in conventional (C-F) and slow-release (ER-F) formulations, 12 patients with essential hypertension underwent ambulatory blood pressure monitoring (ABPM) at the end of a 2-week treatment period with C-F 5 mg b.d., ER-F 10 mg once daily (o.d.) and placebo. C-F, ER-F and placebo were given in a double-blind 3 x 3 latin square design 4 times replicated. There was no systematic change in the ABP profile over the three study periods regardless of the treatment. In comparison to placebo, the mean 24-h systolic and diastolic blood pressures showed a significant and similar reduction after both formulations of F. Compared to placebo, C-F and ER-F induced a significant reduction in systolic blood pressure for 15 and 21 h, respectively, and of diastolic blood pressure for 16 and 21 h, respectively. Three patients complained of headache (mild in 2, moderately severe in 1), and two patients of nocturia, with either formulation of F.

Adult↗
PubMed1990

Inheritance of species-specific behaviors in the paradise fish (Macropodus opercularis): a diallel study.

Species-specific elements of the paradise fish's ethogram were recorded in one familiar and three different unfamiliar environments, which were designed to model certain features of this species' natural habitat: (1) a densely vegetated home range, (2) a novel open field, (3) a small novel place, and (4) a small novel place with a predator. The inheritance of the behavioral elements was investigated employing a five-times-replicated diallel cross among three inbred strains. A detailed Hayman analysis of variance and a variance-covariance analysis were performed to uncover the genetic architectures of these phenotypes. Additive genetic effects and/or ambidirectional dominance was found to be characteristic of most species-specific behavioral elements studied, suggesting an evolutionary history of stabilizing selection.

Animals↗
PubMed2026

Integrative quantum and systems biology of cancer: From molecular fluctuations to ecological outcomes.

This review treats cancer as a multiscale adaptive system, asks what the framework must predict to be worth adopting, and separates at each scale what the evidence establishes from what is proposed. It is an expert narrative synthesis, not a systematic review, and states the limits of that design. Proton transfer and tautomeric shifts contribute to spontaneous mispairing but do not license claims of directed or non-random mutation: replication timing, three-dimensional chromatin organization, sequence context and known mutagenic processes explain most mutational heterogeneity, leaving any quantum contribution as a residual against that baseline. The Waddington quasi-potential is bounded: outside detailed balance the dynamics are not gradient-derivable and require a probability-flux term. Hysteresis, rate-limited bimodality and return to state after perturbation distinguish an attractor from a transcriptomic cluster. Single-cell karyotype and live-imaging evidence supports whole-genome doubling as an unstable intermediate of heterogeneous origin and context-dependent consequence, not a uniform adaptive strategy. Systems and synthetic biology, virtual cells and digital twins are assessed against benchmarks, not promise. Tissue-scale ecology is reported with the spatial measurements now quantifying it, including evidence that stromal niche construction is not uniformly tumor-supporting. RNA modification is a layer in its own right, showing that the interpretation of a regulatory signal, not its magnitude, is biologically decisive. A dedicated section states the framework's commitments, the observable and evidence at each scale, and what would falsify them, asking what this adds to somatic mutation theory with clonal evolution and plasticity.

Neoplasms↗
PubMed2024

ERCC2 mutations alter the genomic distribution pattern of somatic mutations and are independently prognostic in bladder cancer.

Excision repair cross-complementation group 2 (ERCC2) encodes the DNA helicase xeroderma pigmentosum group D, which functions in transcription and nucleotide excision repair. Point mutations in ERCC2 are putative drivers in around 10% of bladder cancers (BLCAs) and a potential positive biomarker for cisplatin therapy response. Nevertheless, the prognostic significance directly attributed to ERCC2 mutations and its pathogenic role in genome instability remain poorly understood. We first demonstrated that mutant ERCC2 is an independent predictor of prognosis in BLCA. We then examined its impact on the somatic mutational landscape using a cohort of ERCC2 wild-type (n = 343) and mutant (n = 39) BLCA whole genomes. The genome-wide distribution of somatic mutations is significantly altered in ERCC2 mutants, including T[C>T]N enrichment, altered replication time correlations, and CTCF-cohesin binding site mutation hotspots. We leverage these alterations to develop a machine learning model for predicting pathogenic ERCC2 mutations, which may be useful to inform treatment of patients with BLCA.

Humans↗
PubMed1991

Chromosome structure and eukaryotic gene organization.

The DNA in the eukaryotic nucleus is highly compacted but well organized into distinct regional units. Chromosomal bands are characterized by their structure and distinctive replication time. They are subdivided into chromatin loops which serve as functional domains that have discrete boundary elements and can be regulated during development.

Animals↗
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↗