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At least 379 records · Page 21Linked to original sources
PubMed2002

Methylation reveals a niche: stem cell succession in human colon crypts.

Little it known about human stem cells although they are likely to be the earliest progenitors of carcinomas. Just as methylation can substitute for mutations to inactivate tumor suppressor genes, methylation can also substitute for mutations in a phylogenetic analysis. This review explains why stem cell dynamics may be important to tumor progression and how methylation patterns found in a normal human colon can be used to reconstruct the behavior of crypt stem cells. Histories are recorded in sequences and strategies used to reconstruct phylogenies from sequences likely apply to methylation patterns because both exhibit somatic inheritance. Such a quantitative analysis of colon methylation patterns infers stem cells live in niches containing multiple 'stem' cells. Although niche stem cell numbers remain constant, clonal succession is inherent to niches because periodically progeny from a single stem cell become dominant. These niche succession cycles may potentially accumulate multiple alterations because they resemble superficially the clonal succession of tumor progression except that they occur invisibly in the absence of selection or phenotypic change. Alterations without immediate selective value may hitchhike passively in the stem cells that become dominant during niche succession cycles. The inherent ability of a niche to fix alterations (Muller's ratchet) is another potential mechanism besides instability and selection to sequentially accumulate multiple alterations. Many alterations found in colorectal tumors may reflect such occult clonal progression in normal colon.

Colon↗
PubMed2001

Genetic conflict and conditional altruism in social aphid colonies.

Although kin selection is central to the modern study of social evolution, recent studies of social species have revealed that no simple relationship exists between levels of kinship and sociality. The soldier-producing aphids are unique among highly social animals because, barring movement by aphids between colonies, they occur in clonal groups of genetically identical individuals. Potentially, clonality simplifies efforts to understand social evolution in aphids by obviating issues of intragroup conflict. However, we report here high levels of clonal mixing and conflict in an aphid society. The gall-dwelling colonies of a social aphid species (Pemphigus obesinymphae) are not pure clones, but are invaded by large numbers of aphids from other clones. Intruders behave and develop selfishly once they have invaded a colony of nonkin. They refrain from risky defensive behaviors and accelerate their own development into reproductive rather than defensive stages. This conditionality in the social life of P. obesinymphae reveals complex dynamics and a degree of behavioral plasticity not previously known in aphid societies.

Animals↗
PubMed2004

Assessment of recombinant porcine follicle-stimulating hormone receptor using a novel polyclonal ectodomain antibody.

Follicle-stimulating hormone (FSH) receptors (FSHR) are critically involved in mediating the responses of granulosa cells and Sertoli cells to FSH. The dynamic changes in cell surface FSH receptors (FSHR) in response to FSH remain unclear in part because of the heavy reliance on ligand-binding methodologies. This study was designed to determine the molecular and cellular properties of recombinant porcine FSHR using a novel, high-affinity purified polyclonal antibody to the ectodomain of the pFSHR. A full-length porcine FSHR cDNA was cloned and sequenced and recombinant pFSHR protein was stably expressed in a clonal cell line of Chinese hamster ovary cells (pFSHR-CHO). Recombinant receptor was stably expressed in an ovarian cell line with a density similar to that of porcine ovarian cells. A specific polyclonal antibody was generated in chickens to a 100-amino acid fragment of the pFSHR ectodomain. Immunoblotting, immunoprecipitation, indirect immunofluorescence cytochemistry and immunoelectron microscopy were performed using affinity-purified antibody to identify recombinant pFSHR in pFSHR-CHO cells. Immunoblotting of solubilized pFSHR-CHO proteins and immunoprecipitation of pFSHR-CHO protein metabolically labeled with 35S identified a single 74-kDa band in pFSHR-CHO cells; no bands were visualized in mock-transfected CHO cells. Indirect immunofluorescent labeling revealed the presence of pFSHR in pFSHR-CHO cells but not in mock-transfected CHO cells. Immunoelectron microscopy revealed the highest density of pFSHR associated with the plasma membrane and no pFSHR in mock-transfected CHO cells. The chicken anti-pFSHR antibody is a valuable tool for detecting and monitoring of FSHR using a variety of methodologies.

Animals↗
PubMed2026

Evidence for the prognostic value of TP53 mutations in circulating tumor DNA across solid malignancies: a systematic review and meta-analysis.

BACKGROUND: The purpose of this meta-analysis study is to provide evidence for the clinical utility of TP53 mutations in circulating tumor DNA (ctDNA) as a prognostic biomarker. METHODS: We searched the PubMed, Embase, Cochrane, and Web of Science databases (last update May 2025) for studies on TP53 mutations in ctDNA or cfDNA as prognosis overall survival and in solid tumors. A total of 21 studies that met the criteria were utilized and data was collected regarding the authors, year of publication, study design, site of the study, number of patients, detection, mutation sample size and outcome measures were collected. The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of the study, and meta-analysis was done by using STATA 16.0. Effect sizes were in the form of hazard ratios (HR) that had 95% confidence intervals (CI). The models used were fixed-effects and random-effects based on heterogeneity. Funnel plots, and Egger's test was used to measure publication bias, and sensitivity analysis conducted through a leave-one-out method. RESULTS: A total of 21 studies (2,685 TP53-mutated patients, one unreported) showed: Mutated patients had worse progression-free survival (PFS) (HR=2.10, p=0.000; 12 studies, heterogeneity resolved after excluding Yoshida 2023), shorter OS (HR=1.74, p=0.014; 9 studies), and reduced DFS (HR=1.73, p=0.007; 3 studies), but RFS (2 items) showed no statistically significant differences. Subgroup analyses revealed: Prospective studies showed stronger PFS (HR=2.14 vs retrospective 1.90) with Japanese subgroup HR=4.90; Lung/liver cancers had higher HRs than breast. Prospective OS HR=2.25 (lung 3.14, endometrial 0.75). Retrospective DFS HR=1.89 vs Japanese breast RFS HR=4.00. Heterogeneity originated from study design, region, and cancer type variations, with no significant publication bias (Egger's test p>0.05). CONCLUSION: Current evidence suggests that TP53 mutations detected in ctDNA are significantly associated with poor prognosis in various solid tumors, particularly lung cancer. The association is robust for PFS and OS, though high heterogeneity and biological complexity warrant cautious interpretation. These findings support the potential incorporation of ctDNA-based TP53 mutation status into clinical prognostic assessment systems as an adjunctive parameter; however, further standardization of detection protocols, functional annotation of mutation types (e.g., LOF vs. GOF), incorporation of VAF and clonality analysis, and validation in large prospective multicenter cohorts are needed before routine clinical implementation. PROSPERO REGISTRATION NUMBER: CRD420251021095.

Humans↗
PubMed2005

Forest fragmentation effects on patch occupancy and population viability of herbaceous plant species.

Habitat fragmentation is one of the major threats to species diversity. In this review, we discuss how the genetic and demographic structure of fragmented populations of herbaceous forest plant species is affected by increased genetic drift and inbreeding, reduced mate availability, altered interactions with pollinators, and changed environmental conditions through edge effects. Reported changes in population genetic and demographic structure of fragmented plant populations have, however, not resulted in large-scale extinction of forest plants. The main reason for this is very likely the long-term persistence of small and isolated forest plant populations due to prolonged clonal growth and long generation times. Consequently, the persistence of small forest plant populations in a changing landscape may have resulted in an extinction debt, that is, in a distribution of forest plant species reflecting the historical landscape configuration rather than the present one. In some cases, fragmentation appears to affect ecosystem integrity rather than short-term population viability due to the opposition of different fragmentation-induced ecological effects. We finally discuss extinction and colonization dynamics of forest plant species at the regional scale and suggest that the use of the metapopulation concept, both because of its heuristic power and conservation applications, may be fruitful.

Biodiversity↗
PubMed2002

Nutrient-toxicant interactions in natural and constructed phytoplankton communities: results of experiments in semi-continuous and batch culture.

Natural communities and clonal cultures of phytoplankton derived from large lakes in Yellowstone National Park (WY, USA) were employed to explore the effects of interactions between resource availability and toxic metals (divalent Cu and Cd) on pelagic plant communities. Results of semi-continuous competition experiments demonstrated strong direct and interactive effects of resource availability and additions of toxic metals (25-150 nmol l(-1)) in both natural and laboratory constructed four-species communities. Both endpoint community composition and population dynamics of individual species elicited responses to interaction between limiting resources and toxic metals. N limited growth in low-density batch cultures was suppressed by addition of Cu and these effects were specific to both algal species and level of available nitrate. Measures of semi-continuous culture effluent pH and pCu demonstrated that high levels of productivity can allow phytoplankton to selectively alter bulk water chemistry in the presence of elevated levels of metals to counteract their toxic effects. Concentrations of both limiting nutrients and toxicants employed were within the range of field-measured levels, suggesting that these types of interactions may be commonplace in natural environments. As such, environmental assessments considering potential impacts of toxic agents should take into account the nutrient status of the aquatic environment, and the interactions among stressors as demonstrated here.

Cadmium↗
PubMed1996

Change of genetic architecture in response to sex.

A traditional view is that sexual reproduction increases the potential for phenotypic evolution by expanding the range of genetic variation upon which natural selection can act. However, when nonadditive genetic effects and genetic disequilibria underlie a genetic system, genetic slippage (a change in the mean genotypic value contrary to that promoted by selection) in response to sex may occur. Additionally, depending on whether natural selection is predominantly stabilizing or disruptive, recombination may either enhance or reduce the level of expressed genetic variance. Thus, the role of sexual reproduction in the dynamics of phenotypic evolution depends heavily upon the nature of natural selection and the genetic system of the study population. In the present study, on a permanent lake Daphnia pulicaria population, sexual reproduction results in significant genetic slippage and a significant increase in expressed genetic variance for several traits. These observations provide evidence for substantial genetic disequilibria and nonadditive genetic effects underlying the genetic system of the study population. From these results, the fitness function of the previous clonal selection phase is inferred to be directional and/or stabilizing. The data are also used to infer the effects of natural selection on the mean and the genetic variance of the population.

Analysis of Variance↗
PubMed2002

Microsatellite analysis of environmental and clinical isolates of the opportunist fungal pathogen Aspergillus fumigatus.

Microsatellite analysis was used to examine the genetic relatedness of 111 clinical and environmental isolates of the opportunist human pathogenic fungus Aspergillus fumigatus from Ontario, Canada. Forty-three A. fumigatus isolates were from clinical sources and 68 from environmental sources. Phylogenetic analysis of the genotypes revealed that there were no geographical or temporal associations of clinical or environmental genotypes. In fact, several of the environmental and clinical isolates showed identical (clonal) genotypes from disparate geographical areas. However, a locus by locus examination revealed that there were several significant differences in allele frequencies between clinical and environmental isolates. There may be linkage of certain microsatellite loci with genes affecting virulence in A. fumigatus. A susceptible individual may be equally predisposed to infection by any isolate of A. fumigatus. However, under transient selection as a pathogen, genes encoding alleles for enhanced virulence may not assort independently from microsatellite loci. A dynamic equilibrium may exist between random recombination of loci in the natural environment and selection for virulence factors during host infection cycles.

Aspergillosis↗
PubMed2005

Comparative selection of the K65R and M184V/I mutations in human immunodeficiency virus type 1-infected patients enrolled in a trial of first-line triple-nucleoside analog therapy (Tonus IMEA 021).

Tonus was a pilot study in which previously untreated human immunodeficiency virus type 1 (HIV-1)-infected patients received the combination of abacavir, lamivudine, and tenofovir once a day. There was a high rate of early virological failure, and the M184V and K65R mutations were frequently detected at week 12 (W12). The objective of this study was to examine the selection dynamics of the K65R and M184V/I mutations. Bulk sequencing of the reverse transcriptase (RT) gene was performed on plasma HIV-1 RNA at baseline, W4, and W12 for 21 patients with detectable viral loads. The RT genes from baseline, W4, and W12 plasma samples from five patients who developed both M184V and K65R but with different mutational patterns were also cloned and screened for the K65R mutation by selective real-time PCR. At baseline, bulk sequencing and clonal analysis showed only wild-type RT sequences. At W4, M184V/I was detected in 12/19 patients and K65K/R in 2 patients by bulk sequencing. At W12, M184V/I was found in 18/20 patient, together with the K65R in 13 patients. At W4, clonal analysis revealed the K65R mutation in 0.6 to 48% of clones in the five patients studied. At W12, the K65R mutation was found in 30 to 100% of clones. K65R and M184V/I seemed to arise in separate clones, followed by an enrichment of viruses containing both mutations. The clinical relevance of this independent evolution is unclear. M184V/I was selected more frequently than K65R at W4. However, K65R was also detected early using a clone-sensitive genotyping method. All three nucleoside analogs are known to select the K65R and/or M184V/I mutation. This convergent genetic pathway to resistance, associated with lower antiretroviral potency, may explain the high selection rate of these mutations in this trial.

Adenine↗
PubMed1991

Clonal, in vivo behavior of the totipotent hematopoietic stem cell.

Classical and more recent studies have provided a description of the in vivo behavior of the totipotent hematopoietic stem cell and its clonal progeny. These reconstitution experiments, employing clonotypic markers have shown that single or few engrafted lymphoid-myeloid stem cells are both necessary and sufficient for long-term, stable hematopoiesis in a reconstituted mouse. This underscores the remarkable developmental capacity of individual stem cell clones. Furthermore, the long-term and retransplantation studies have provided an indication of stem cell self-renewal ability. Taken together, the long-term analyses have also shed light on the dynamic behavior of engrafted stem cell clones and of the entire reconstituted hematopoietic system. A model is presented where the developmental and proliferative behavior of totipotent stem cells is a function of time. In this model commitment versus self-renewal decisions may be governed by stochastic mechanisms. However, the actual contribution by stem cells to particular mature cell populations may be more a function of lineage specific demands as they change over post-engraftment time.

Animals↗
PubMed1992

Dynamic changes in cytokine secretion by stromal cells during prolonged maintenance under protein-free conditions.

Stromal cells of bone marrow origin produce a variety of known cytokines and some factors exhibiting apparently new biological activities. Several of these were identified by the study of cell to cell interactions and were not found in detectable amounts in media conditioned by the cells. We describe here a culture system that enables the release of stromal cytokines into medium free of any added proteins and supplemented with peptides from casein hydrolysate (0.1%). The absence of serum proteins allows extensive concentration and monitoring of activities that are otherwise undetectable. Stromal cells of the MBA-2.1 clonal cell line were seeded in a stationary bed reactor packed with a carrier of non-woven fabric matrix. After a proliferation phase with serum containing medium, the cells were maintained for over 10 months in protein-free medium. Throughout this extended incubation in the absence of serum or serum replacing proteins, stromal cells retained their viability and continuously released transforming growth factor-beta (TGF-beta), macrophage-colony stimulating factor (M-CSF) and restrictin-P, a cytotoxic factor that specifically arrested the growth of plasmacytoma cells. In addition, interleukin-6 (IL-6) was first undetectable, and later in culture its titer reached a maximum of 180,000 international units (IU)/ml. Concomitantly, the production of restrictin-P diminished and reached its lowest levels at the end of 10 months. The results may imply a possible causal relationship between the expression of IL-6 and restrictin-P, since no similarly significant changes were observed in the titers of M-CSF and TGF-beta. This novel bioreactor system may be adaptable for efficient production of different cytokines under absolute serum-free conditions.

Animals↗
PubMed2002

Stochastic gene expression in a single cell.

Clonal populations of cells exhibit substantial phenotypic variation. Such heterogeneity can be essential for many biological processes and is conjectured to arise from stochasticity, or noise, in gene expression. We constructed strains of Escherichia coli that enable detection of noise and discrimination between the two mechanisms by which it is generated. Both stochasticity inherent in the biochemical process of gene expression (intrinsic noise) and fluctuations in other cellular components (extrinsic noise) contribute substantially to overall variation. Transcription rate, regulatory dynamics, and genetic factors control the amplitude of noise. These results establish a quantitative foundation for modeling noise in genetic networks and reveal how low intracellular copy numbers of molecules can fundamentally limit the precision of gene regulation.

Bacterial Proteins↗
PubMed2001

Population structure and ecology of a tropical rare rhizomatous species of teosinte Zea diploperennis (Gramineae).

One of the objectives of the Sierra de Manantlán Biosphere Reserve (Jalisco, México) is the conservation in situ of the teosinte Zea diploperennis Iltis, Doebley, Guzman & Pazzi. Zea diploperennis is perennial, shade intolerant and its 1-3 m shoots are architecturally similar to maize. Clonal growth is of the phalanx type. Genets are iteroparous (modules semelparous). The demography of seven module and genet populations was studied in seven sites representing three stages of old-field succession. Seven permanent one-meter-square plots were randomly established in each site. All genets initially present and those that became established during our study were mapped and labeled according to year of establishment. The magnitude of demographic fluctuations was greater in module populations. Genet population dynamics followed a seasonal rhythm with a maximum population size obtained at the onset of the rainy season. A relation was documented between percent annual mortality of a cohort and its age: the younger the cohort, the greater the mortality. This was a statistically significant relationship, Y = [sin(-0.288x + 1.657)]2 (r = 0.92, p < 0.01), where is proportion annual mortality of genets and is the age of the cohort. The maximum rates of genet mortality occurred during the rainy season when population densities were greatest. As a consequence, we postulate that competition occurs principally during the rainy season. Linear relationships were observed between rate of population increase of genets versus old-field successional stage and soil type. Those areas with poor soil (Ultisol), degraded soil or soils with similar physical characteristics could be rehabilitated by introducing Z. diploperennis. Such rehabilitation would achieve two distinct objectives, promote propagation of this rare endemic and reclaim areas that are susceptible to erosion and further degradation.

Biodegradation, Environmental↗
PubMed1996

Expansion of mutant stem cell populations in the human colon.

In general, it is presumed that colonic epithelial stem cells are the principal cell type at risk of incurring the series of somatic mutations leading to carcinoma, since all other epithelial cell types are short-lived. Mutant stem cell clonal expansion increases the risk for subsequent mutations and is therefore a potentially important step in carcinogenesis. The stem cells reside in colonic crypts, simple tubular foldings of the epithelium, and thus counting crypts provides an indirect means to determine stem cell numbers. The normal crypt population is known to expand through a process of crypt replication and this is thought to result in a corresponding expansion of the epithelial stem cell population. A simple mathematical model of the population dynamics of normal and mutant crypts (crypts containing mutant stem cells) is developed and used to estimate a lower bound on the relative rate of expansion of the mutant stem cell population. The model predicts that if mutant and normal crypt populations expand at the same rate, and if the mutation rate is small relative to the rate of growth, then the fraction of clusters of mutant crypts composed of only a single mutant crypt should steadily decrease with age towards one-half. Aberrant crypts are easily recognizable lesions in human colon which have frequently been shown to contain cells with K-ras and occasionally APC gene mutations. Application of the model to recent counts of aberrant crypt cluster sizes indicate that the aberrant crypt population, and the contained mutant stem cell population, is expanding substantially faster than normal.

Cell Division↗
PubMed2006

Individual stem cells with highly variable proliferation and self-renewal properties comprise the human hematopoietic stem cell compartment.

Hematopoiesis requires tight regulation of the hematopoietic stem cell (HSC) population; however, the dynamics of HSC use at steady state are uncertain. Over 3-7 months, we evaluated the repopulation and self-renewal of more than 600 individual human 'severe combined immunodeficiency mouse-repopulating cells' (SRCs), tracked on the basis of lentiviral integration sites, in serially transplanted immune-deficient mice, as well as of SRC daughter cells that migrated to different marrow locations in a single mouse. Our data demonstrate maintenance by self-renewing SRCs after an initial period of clonal instability, a result inconsistent with the clonal succession model. We found wide variation in proliferation kinetics and self-renewal among SRCs, as well as between SRC daughter cells that repopulated equivalently, suggesting that SRC fate is unpredictable before SRCs enter more rigid 'downstream' developmental programs.

ADP-ribosyl Cyclase 1↗
PubMed1990

The ecology and evolution of inducible defenses.

Inducible defenses are responses activated through a previous encounter with a consumer or competitor that confer some degree of resistance to subsequent attacks. While the importance of inducible resistance has long been known in host-parasite interactions, it is only recently that its importance has emerged in other natural systems. Although the structural defenses produced by invertebrates to their competitors and predators are by no means the same as an immune response triggered by parasites, these responses all share the properties of (1) specificity, (2) amplification and (3) memory. This review discusses the following ecological consequences and evolutionary causes of inducible defenses: (1) Inducible defenses render historical factors important in biological interactions and can affect the probability of individual survival and growth, as well as affect population dynamics of consumers in some circumstances. (2) Although the benefits of inducible defenses are often balanced by fitness costs, including reduced growth, reproductive output and survivorship, the role of costs and benefits in the evolution of inducible defenses is by no means clear. A more integrated approach would involve a multivariate analysis of the role of natural selection on the inducible characters of interest, their norms of reaction and correlated fitness characters. (3) The disproportionate representation of inducible, morphological defenses among clonal organisms may be due to both a higher rate of origination and enhanced selection to maintain these defenses in clonal taxa. (4) Inducible defenses should be most common when reliable cues are available, attacks by biological agents are unpredictable, and the fitness gains of defenses are balanced by the costs. An integrated approach to studying inducible defenses would thus combine mechanistic estimates of costs, population-level estimates of defense effectiveness, and genetic estimates of correlations between fitness and inducible characters. This will allow us to estimate rates of evolution in these phenotypically plastic threshold characters.

Animals↗
PubMed1997

Clonality and life cycles of intestinal crypts explained by a state dependent stochastic model of epithelial stem cell organization.

The organization and control of stem cells is a key issue in epithelial cell biology. The small intestinal murine crypt is a useful tissue to study such problems since stem cells are known to be located at specific positions at the bottom of the crypt where they are self maintaining. Recent data suggest, that (1) the number of active stem cells in a crypt can fluctuate, (2) the immediate progeny of a single stem cell can replace other stem cells eventually leading to monoclonality and (3) the life cycle of crypts may be linked to stem cell dynamics. It is the objective of this paper to suggest a stochastic state-dependent model of stem cell and crypt growth which can explain and-link these phenomena into one comprehensive framework. Monte Carlo simulations are performed to show consistently with available data. The model explains the size distribution of small intestinal crypts in steady state, the observations of stem cell fluctuations and monoclonality conversion, recovery of the crypt population after moderate damage and the rate of crypt fission and extinction. The key assumption of this model is an autoregulatory control of stem cell growth.

Animals↗
PubMed1998

Heteroplasmy and organelle gene dynamics.

This study assesses factors that influence the rates of change of organelle gene diversity and the maintenance of heteroplasmy. Losses of organelle gene diversity within individuals via vegetative segregation during ontogeny are paramount to resultant spatial and temporal patterns. Steady-state losses of organelle variation from the zygote to the gametes are determined by the effective number of organelles, which will be approximately equal to the number of intracellular organelles if random segregation prevails. Both rapid increases in organelle number after zygote formation and reductions at germ lines will reduce variation within individuals. Terminal reductions in organelles must be to very low copy numbers (<5) for substantial losses in variation to occur rapidly. Nonrandom clonal expansion and vegetative segregation during gametogenesis may be effective in reducing genetic variation in gametes. If organelles are uniparentally inherited, the asymptotic expectations for effective numbers of gametes and spatial differentiation will be identical for homoplasmic and heteroplasmic conditions. The rate of attainment of asymptote for heteroplasmic organelles, however, is governed by the rate of loss of variation during ontogeny. With sex-biased dispersal, the effective number of gametes is maximized when the proportional contributions of the sex having the higher dispersal rate are low.

Animals↗