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PubMed2005

Dynamics of pneumococcal carriage among healthy Icelandic children attending day-care centres.

Invasive pneumococcal disease and antimicrobial (AM) resistance in pneumococci are important public health concerns. With the advent of new pneumococcal vaccines, information on serotype prevalence and their temporal fluctuations is important. Information on AM use and consent for participation was obtained by a questionnaire to parents of children at 5 day-care centres in Reykjavik from 1992 to 1999, and nasopharyngeal swabs were cultured selectively for pneumococci. The pneumococci were serotyped and pulsed field gel electrophoresis used to determine clonality. Of 1228 nasopharyngeal swabs, 640 (52.1%) yielded pneumococci of which 89 (13.9%) had decreased susceptibility to penicillin and 1 was resistant. Children receiving AMs during the month preceding nasopharyngeal sampling and children attending a day-care centre where AM use was high were significantly more likely to carry penicillin non-susceptible isolates. Serotypes 6A, 6B and 23F were most common (48%), and 74% of serotyped isolates belonged to 1 of the 7 most common serotypes. Almost all penicillin non-susceptible isolates were of serotype 6B or 19A. Serotype prevalence fluctuated markedly between y. In conclusion, there was significant variation in serotype prevalence between y, and only 51% of the pneumococci belonged to serotypes covered by the current 7-valent conjugated vaccine.

Anti-Bacterial Agents↗
PubMed1994

Dynamic changes of accumulated T cell clonotypes during antigenic stimulation in vivo and in vitro.

It has not been known how T cell clones respond to antigenic stimulation. We applied reverse transcription polymerase chain reaction and subsequent single-strand conformation polymorphism (SSCP) analysis to monitor the kinetics of accumulated T cell clonotypes with respect to the TCR beta chain. Before exposure to an antigen, peripheral blood lymphocytes from healthy individuals exhibited smears with SSCP, indicating a heterogeneous T cell population. However, some bands were demonstrated within the smears, each corresponding to a distinct clonal accumulation. The majority of the accumulated clones were CD8+ and were stably detected over 1 year in the same individual. Next it was demonstrated that a number of clonal accumulations appeared in a diverse population after an acute infection in vivo or in cell culture with an antigen in vitro. The accumulations in vivo were demonstrated in both the CD4+ and CD8+ subsets, the latter having the longer duration of response after stimuli. On the other hand, in vitro culture with purified protein derivative induced expansions of a number of CD4+ clones throughout the culture, while CD8+ clones were shown to be induced later. There was no preferential usage of particular V beta genes in these clonotypes. Stimuli by more simple peptides could also induce clonal expansions of T cells. Therefore, with our novel experimental system, we could monitor the kinetics of T cell clonotypes induced by an antigen. This method may be applied to analyses of T cell clonality in many kinds of immune responses.

Adult↗
PubMed1994

Cellular site of synthesis and dynamics of cell surface re-expression of polysialic acid of the neural cell adhesion molecule.

Homopolymers of alpha-2,8-ketosidically linked sialic acid (polysialic acid) represent a posttranslational modification which, in mammals, appears to be unique for the neural cell adhesion molecule and the alpha subunit of sodium channels in brain. Under steady-state conditions, polysialic acid is detectable in the plasma membrane of different cell types but not in the cytoplasm. We have studied the site of synthesis and the cell surface re-expression of polysialic acid in a clonal subline of small cell lung carcinoma using the monoclonal antibody 735 and bacteriophage endosialidase, both specific reagents for polysialic acid. After enzymic removal, cell surface polysialic acid re-expression reached control levels only after 5 days. When Golgi to plasma membrane transport of endosialidase-treated cells was blocked by culture at 20 degrees C or in the presence of monensin at 37 degrees C, de-novo-synthesized polysialic acid became detectable in the Golgi apparatus. Our data show that synthesis of polysialic acid of the neural cell adhesion molecule with a degree of polymerization of at least nine occurs intracellular in the Golgi apparatus of a human small cell lung carcinoma cell line.

Animals↗
PubMed2003

Molecular tracking of antigen-specific T cell clones in neurological immune-mediated disorders.

T cells recognizing self or microbial antigens may trigger or reactivate immune-mediated diseases. Monitoring the frequency of specific T cell clonotypes to assess a possible link with the course of disease has been a difficult task with currently available technology. Our goal was to track individual candidate pathogenic T cell clones, selected on the basis of previous extensive studies from patients with immune-mediated disorders of the CNS, including multiple sclerosis, HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) and chronic Lyme neuroborreliosis. We developed and applied a highly specific and sensitive technique to track single CD4(+) and CD8(+) T cell clones through the detection and quantification of T cell receptor (TCR) alpha or beta chain complementarity-determining region 3 transcripts by real-time reverse transcriptase (RT)-PCR. We examined the frequency of the candidate pathogenic T cell clones in the peripheral blood and CSF during the course of neurological disease. Using this approach, we detected variations of clonal frequencies that appeared to be related to clinical course, significant enrichment in the CSF, or both. By integrating clonotype tracking with direct visualization of antigen-specific staining, we showed that a single T cell clone contributed substantially to the overall recognition of the viral peptide/MHC complex in a patient with HAM/TSP. T cell clonotype tracking is a powerful new technology enabling further elucidation of the dynamics of expansion of autoreactive or pathogen-specific T cells that mediate pathological or protective immune responses in neurological disorders.

Adult↗
PubMed1991

7th Jan Waldenström Lecture. The biology of human cancer metastasis.

The process of cancer metastasis is dynamic and consists of sequential, interrelated steps. Malignant cells that produce metastases have survived a series of potentially lethal interactions that are regulated by both the intrinsic properties of the tumor cells and host factors. Although some of the steps in this process contain stochastic elements, metastases develop from the nonrandom survival of a few subpopulations of cells that preexist within the parent neoplasm. Metastases can have a clonal origin, and different metastases can originate from the proliferation of different cells. The orthotopic implantation of human cancer cells derived from surgical specimens into nude mice provides a biological model of metastasis. Using this model, clonal analysis of a human renal carcinoma, colon carcinoma, and melanoma has revealed that these tumors are heterogeneous for metastatic properties. Damage to an organ's environment is followed by inflammation and repair, and these homeostatic processes facilitate the proliferation of normal (physiology), and in some cases, tumor cells (pathology). Accelerated growth of human colon cancer cells was found in hepatectomized nude mice, whereas accelerated growth of human renal cancer cells was found in nephrectomized nude mice. These data suggest that systemic physiological signals can be usurped by neoplastic cells. Collectively, the factors that regulate metastasis are the intrinsic properties of metastatic cells and host factors involved in homeostasis.

Animals↗
PubMed1991

Scaling concepts in cellular and subcellular dynamics.

After developing a map for certain states typical of hemopoietic stem cells (SCs), we identify a number of parameters (e.g. fractal dimensions, oscillatory behavior in a multistable landscape, etc.) that scale down to subcellular structures such as interphase genome, chromatids, chromatin entanglements and DNA segmental motions. A curious aspect is the continuous reappearance of recursive processes even at very small biologic scales. These iterations are relevant not only for the normal behavior of (hemopoietic) cells but also for amplifying hidden genomic singularities above some critical threshold. When that happens, there are sudden quali-quantitative and often clonal changes in the cell behavior. As illustrated by specific leukemic cases, many paradoxes of malignant growth seem best explained by the peculiar sensitivity to initial condition of (hemopoietic) cells. Interpreted as chaotic oscillators, these cells display a spectrum of disorders that, in spite of appearing as random, are in fact triggered by amplification of subtle preconditions with statistico-deterministic outcomes, that are predictable within certain time limits.

Animals↗
PubMed2002

[Architectural plasticity of the stoloniferous herb, Duchesnea indica in response to different elevation].

Architectural plasticity of clonal plant may modify its ways of utilization of resources through clonal growth and be of ecologically importance. The plasticity of clonal architecture in response to ecological conditions at different altitudes in a stoloniferous herb, Duchesnea indica, was investigated in an experiment with different elevations of 400, 800, 1200, and 1600 m. The results showed that the change patterns of spacer length, ramet density, branching intensity, and branching angle of Duchesnea indica were in a quadratic curve when the elevation increased. The architectural plasticity of D. indica was simulated through dynamic Logistic model, and the imitative effect was statistically preferable. Combining with the resources utilization of Duchesnea indica under different environments, the architectural plasticity was also discussed in this paper.

Altitude↗
PubMed2003

Dynamics of the penA gene in serogroup C meningococcal strains.

The transpeptidase encoding region of the penA gene was sequenced in 44 meningococcal strains (41 serogroup C [23 characterized as serotype 2b and 18 as serotype 2a] and 3 serogroup B [B:2b:P1.2,5]). All strains were characterized by multilocus sequence typing and were determined to be susceptible or intermediate resistant to penicillin (Pen(s) or Pen(i), respectively). A high degree of homology was found among the penA alleles identified in the Pen(s) strains. All the Pen(i) C:2b strains, which belonged to 2 different clonal complexes, showed the same penA gene allele. This fact suggests that 1 of the clonal complexes acquired that allele, spreading it to the other by horizontal transfer. The same allele also was found in the B:2b strains studied, indicating that 1 of the Pen(i) C:2b strains underwent a capsular switching event. A different mosaic penA allele was identified in the Pen(i) C:2a strains, which belonged to the ET37 cluster.

Alleles↗
PubMed2003

Regulation of nuclear translocation of nuclear factor-kappaB relA: evidence for complex dynamics at the single-cell level.

We have analysed activation of nuclear factor-kappaB (NF-kappaB) in response to interleukin-1 (IL-1) in human fibroblasts by tracking intracellular distribution and levels of endogenous relA, NF-kappaB1 and inhibitor of kappaB (I-kappaB) alpha using semi-quantitative confocal microscopy. Nuclear translocation of endogenous relA correlated with I-kappaBalpha degradation during stimulation with IL-1, whereas no effects were seen on levels or localization of NF-kappaB1. During pathway activation, relA was transported up a concentration gradient, resulting in a 3-4-fold increase in nuclear levels, but without any significant decrease in cytoplasmic concentration. IL-1 stimulation caused translocation of only 20% of the relA, but resulted in degradation of up to 70% of the cytoplasmic I-kappaBalpha. RelA nuclear translocation in fibroblasts correlated with DNA-binding activity measured by electrophoretic mobility shift assay (EMSA), both with respect to kinetics and IL-1 concentration-dependence. Clonal populations of cells demonstrated a marked degree of heterogeneity in the response to IL-1. The single-cell assay revealed the presence of responder and non-responder subpopulations, with an enhanced proportion of responder cells, and prolonged responses at higher concentrations of IL-1. Comparing different cell types demonstrated that whereas HepG2 cells, as fibroblasts, showed good correlation between nuclear translocation of relA and activation of DNA binding by relA-containing dimers, EL4 thymoma cells showed no effect on relA localization, even during induction of significant levels NF-kappaB activity, as measured by EMSA. The analysis shows that stimulation by IL-1 results in transient perturbation of the NF-kappaB system, which cycles between the resting and active states with net redistribution of a minor proportion of its DNA-binding component. In addition, it demonstrates significant cell-to-cell variations, as well as cell-type-specific differences in net relA nuclear transport in response to stimuli. The data are consistent with NF-kappaB constituting a dynamic and versatile system, regulated to a significant degree by binary events involving bidirectional trafficking between the cytoplasmic and nuclear compartments during pathway activation.

Active Transport, Cell Nucleus↗
PubMed2004

Presence and localization of T-cell subsets in relation to melanocyte differentiation antigen expression and tumour regression as assessed by immunohistochemistry and molecular analysis of microdissected T cells.

Melanoma-associated antigens may be the driving force behind the lymphocytic infiltrates in melanomas and the occurrence of melanoma regression. To investigate the clinical relevance of melanoma differentiation antigens (MDAs) as T-cell targets, the relationship between the presence and localization of T-cell subsets and the expression of MDAs was studied by immunohistochemistry and the diversity of CD8+ T cells in regressive melanomas was assessed using laser-assisted microdissection. While MDA expression as well as T-cell subset distribution, as assessed by immunohistochemical analysis, was heterogeneous within and between lesions, they were histologically independent phenomena. In four lesions studied in detail by PCR analysis of microdissected T cells, a limited T-cell diversity and evidence for clonally expanded tumour infiltrating lymphocytes were found. However, no major differences in T-cell diversity, as assessed by PCR analysis, between peri-and intra-tumoural areas became apparent, this despite the known clinical significance of the specific localization of a T-cell infiltrate. T cells of clonal origin did not show preferential localization to regressive tumour areas. Moreover, clonally related cells were found in two lesions with a non-brisk infiltrate, while in two lesions with a brisk infiltrate (clinically, a good prognostic factor) no evidence for clonally expanded tumour infiltrating lymphocytes was found. These data support the notion that specific immune reactivity and homing of specific cells to the tumour can occur in melanoma patients. However, they also show that the presence of clonally expanded T cells in the tumour is not necessarily associated with an effective anti-tumour immune response and may, for instance, represent regulatory cells. It appears that the clinical impact of an anti-tumour immune response is largely decided at the tumour site, where micro-environmental conditions dictate the functional state of the T cells. Full understanding of these processes can only be achieved by performing more dynamic analyses of the local host-tumour interactions.

Antigens, Neoplasm↗
PubMed2002

Cytogenetic and molecular genetic aspects of essential thrombocythemia.

Essential thrombocythemia (ET) is a chronic myeloid disorder that is characterized by thrombocytosis, thrombohemorrhagic and vasomotor symptoms, a long median survival, and a low risk of transformation to leukemia. ET can be difficult to distinguish from secondary (reactive) thrombocytosis, and the diagnosis of ET can only be made after the exclusion of other marrow disorders with similar features. Although ET has been assumed to be a clonal process, recent studies have suggested that a substantial number of cases classified as ET may actually not be clonal, and nonclonality may be associated with a lower risk of thrombosis. The lack of a characteristic cytogenetic marker for ET confounds analyses of clonality and offers no insight into disease pathogenesis. There is controversy over the proper classification of thrombocytosis associated with the pathological BCR-ABL gene rearrangement; such cases are not clearly distinguishable from chronic myelogenous leukemia (CML) and should be provisionally classified as CML. New insights are emerging into the role of the megakaryocytopoiesis regulator thrombopoietin (TPO) and its receptor, c-Mpl, in ET and related disorders, but TPO-Mpl dynamics appear to be complex. In some familial thrombocythemic syndromes, mutations in the 5' untranslated region of TPO have recently been described, but these have not yet been observed in sporadic ET. In the future, global analysis of gene expression patterns may help overcome diagnostic dilemmas, refine disease classification, and lead to an improved understanding of the pathogenesis of ET.

Chromosome Aberrations↗
PubMed2003

Biologically motivated computational modeling of formaldehyde carcinogenicity in the F344 rat.

Formaldehyde inhalation at 6 ppm and above causes nasal squamous cell carcinoma (SCC) in F344 rats. The human health implications of this effect are of significant interest since human exposure to environmental formaldehyde is widespread, though at lower concentrations than those that cause cancer in rats. In this article, which is part of a larger effort to predict the human cancer risks of inhaled formaldehyde, we describe biologically motivated quantitative modeling of the exposure-tumor response continuum in the rat. An anatomically realistic, three-dimensional fluid dynamics model of the F344 rat nasal airways was used to predict site-specific flux of formaldehyde from inhaled air into tissue, since both SCC and preneoplastic lesions develop in a characteristic site-specific pattern. Flux into tissue was used as a dose metric for two modes of action, direct mutagenicity and cytolethality-regenerative cellular proliferation (CRCP), which in turn were linked to key parameters of a two-stage clonal growth model. The direct mutagenicity mode of action was represented by a low dose linear dose-response model of DNA-protein cross-link (DPX) formation. An empirical J-shaped dose-response model and a threshold model fit to the empirical data were used for CRCP. In the clonal growth model, the probability of mutation per cell generation was a function of the tissue concentration of DPX while the rate of cell division was calculated from the CRCP data. Maximum likelihood methods were used to estimate parameter values. Survivor (a nontumor outcome) and tumor data for controls from the National Toxicology Program database and from two formaldehyde inhalation bioassays were used for likelihood calculations. The J-shaped dose-response for CRCP provided a better description of the SCC data than did the threshold model. Sensitivity analyses indicated that the rodent tumor response is due to the CRCP mode of action, with the directly mutagenic pathway having little, if any, influence. When evaluated in light of modeling and database uncertainties, particularly the specification of the clonal growth model and the dose-response data for CRCP, this work provides suggestive though not definitive evidence for a J-shaped dose-response for formaldehyde-mediated nasal SCC in the F344 rat.

Administration, Inhalation↗
PubMed2002

Long-term support of hematopoiesis by a single stem cell clone in patients with paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem cell disorder characterized by clonal blood cells that are deficient in glycosylphosphatidylinositol-anchored proteins because of somatic mutations of the PIG-A gene. Many patients with PNH have more than one PNH clone, but it is unclear whether a single PNH clone remains dominant or minor clones eventually become dominant. Furthermore, it is unknown how many hematopoietic stem cells (HSCs) sustain hematopoiesis and how long a single HSC can support hematopoiesis in humans. To understand dynamics of HSCs, we reanalyzed the PIG-A gene mutations in 9 patients 6 to 10 years after the previous analyses. The proportion of affected peripheral blood polymorphonuclear cells (PMNs) in each patient was highly variable; it increased in 2 (from 50% and 65% to 98% and 97%, respectively), was stable in 4 (changed less than 20%), and diminished in 3 (94%, 99%, and 98% to 33%, 57%, and 43%, respectively) patients. The complexity of these results reflects the high variability of the clinical course of PNH. In all patients, the previously predominant clone was still present and dominant. Therefore, one stem cell clone can sustain hematopoiesis for 6 to 10 years in patients with PNH. Two patients whose affected PMNs decreased because of a decline of the predominant PNH clone and who have been followed up for 24 and 31 years now have an aplastic condition, suggesting that aplasia is a terminal feature of PNH.

Adult↗
PubMed2001

[Age-structure dynamics and genetic consequences of Hippophea rhamnoides L. subsp sinensis clone population in Mu Su sandland].

Based on the measurement of all individuals of population at different successional stage, the investigation on edge dispersal effect and the following excavation of clones, the dynamics of age structure and genetic consequences of Hippophea rhamnoides L. subsp sinensis clone population in Mu Su sandland were examined. The results showed that the age structure of the clone population was characterized by a transformation from an increasing type in the early period starting from the initial colonization through a stable type to a declining type. The clone population could maintain or recover its stability by edge dispersal and gap regeneration with clonal growth. As the population self-thinned, the composition of clone population changed from more clones with less ramets to less clones with more ramets and the genetic diversity of clone population decreased.

Age Factors↗
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↗
PubMed1983

Restricted adult clonal profiles induced by neonatal immunization. Influence of suppressor T cells.

The effects of neonatal antigen exposure on the adult B cell repertoire have been examined by characterizing the influenza hemagglutinin (HA)-specific response of adult BALB/c mice given antigen soon after birth. Ligand exposure during early life exerts a profound and lasting effect upon the B cell repertoire, characterized by the expansion and preservation of particular antigen-reactive clones and the apparent loss of others. The precise subset of clonotypes selectively preserved depends upon the age at which antigen is first encountered; and is predictable given a knowledge of the emerging primary pool's dynamics and composition. The preserved (secondary) B cells differ from their unprimed precursors with respect to (a) expression of the surface marker detected by the monoclonal antibody J11d, and (b) susceptibility to T cell-mediated suppression. These studies thus demonstrate a strong relationship between the heritable dynamics of the emerging primary B cell repertoire and the effect of ligand-driven events upon repertoire phenotype. In addition, they provide a mechanistic model for certain forms of antigen-induced oligoclonal dominance, especially the phenomenon of original antigenic sin.

Aging↗
PubMed2003

Dynamics of cytokine generation in patients with active pulmonary tuberculosis.

PURPOSE OF REVIEW: Cytokines have been implicated in the protective immunity, pathophysiology and development of tuberculosis. Most people who become infected with Mycobacterium tuberculosis mount an effective protective immune response, but 5-10% develop disease. Active pulmonary tuberculosis can be considered to reflect an ineffective immune response against mycobacterial infection. A better understanding of how cytokine production contributes to immunity and pathology would aid the development of new vaccines and therapeutic strategies. RECENT FINDINGS: At the time of diagnosis, production of M. tuberculosis or mycobacterial antigen-induced interferon-gamma by peripheral blood mononuclear cells from tuberculosis patients is usually depressed, compared with that of healthy control subjects, whereas cytokine production at the site of disease is elevated. In most patients, depressed interferon-gamma production by peripheral blood mononuclear cells seems to be a transient response because it is significantly increased in most active tuberculosis patients during and following successful antituberculous therapy. However, some patients remain anergic in vivo and in vitro after chemotherapy, and the underlying biochemical mechanisms for T cell anergy in modulating protection or pathology in tuberculosis needs further clarification. Among the cytokines contributing to protective immunity, interleukins 12 and 18, and tumour necrosis factor-alpha are important, the basis of recent studies with tuberculosis patients. SUMMARY: A more complete understanding of cytokine dynamics in individual cells in active pulmonary tuberculosis patients will provide further knowledge about immunopathogenesis and protective immunity in human tuberculosis. This should ultimately enhance development of preventive and therapeutic strategies against this enormously successful intracellular pathogen.

Antitubercular Agents↗
PubMed2005

Intriguing asexual life in marginal populations of the brown seaweed Fucus vesiculosus.

Reproduction of attached large brown algae is known to occur only by sexual zygotes. Using microsatellites we show evolution of asexual reproduction in the bladder wrack promoting population persistence in the brackish water Baltic Sea (< 6 psu). Here a dwarf morph of Fucus vesiculosus is dominated by a single clone but clonal reproduction is also present in the common form of the species. We describe a possible mechanism for vegetative reproduction of attached algae, and conclude that clonality plays an important role in persistence and dispersal of these marginal populations, in which sexual reproduction is impaired by low salinity.

Biological Evolution↗