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PubMed2005

Mechanical perturbation affects conductivity, mechanical properties and aboveground biomass of hybrid poplars.

Xylem development in trees is affected by dynamic mechanical stresses imposed on stems by wind. To assess clonal differences in response to mechanical perturbation (MP), we subjected seven greenhouse-grown F1 hybrids of Populus trichocarpa Torr. and A. Gray. x P. deltoides Bartr. ex Marsh. to a standard MP treatment consisting of 20 manually imposed stem flexures per day for 70-90 days. Effects of MP on aboveground biomass, hydraulic conductivity (k(h)), specific conductivity (k(s)), flexural stiffness (EI), modulus of elasticity (MOE) and modulus of rupture (MOR) were determined. Treatment increased stem radial growth and decreased height growth, leaf area and total aboveground biomass. It also significantly decreased k(s), MOE and MOR, but significantly increased EI and wood specific gravity in most clones. Mechanical perturbation caused greater stem rigidity, without having a significant effect on whole-stem k(h) or percent loss of conductivity due to embolism. Maximum k(h) was positively correlated with EI in both control (r(2) = 0.54, P < 0.0001) and MP-treated (r(2) = 0.61, P < 0.0001) plants, and k(s) and MOE were positively correlated with percent vessel lumen area (r(2) = 0.45, P < 0.0001 and r(2) = 0.28, P = 0.002, respectively). Thus, contrary to our expectation of a trade-off between conductivity and wood strength, there may be an opportunity to select clones for woody biomass production that are superior in both mechanical strength and hydraulic conductivity, as is the triploid Clone 19-61.

Biomass↗

PubMed2007

Detectable minimal residual disease before allogeneic hematopoietic stem cell transplantation predicts extremely poor prognosis in children with acute lymphoblastic leukemia.

BACKGROUND: The level of minimal residual disease (MRD) prior to allogeneic hematopoietic stem cell transplantation (HSCT) has been shown to be an independent prognostic factor for outcome of pediatric patients with high-risk acute lymphoblastic leukemia (ALL). Retrospective studies which used (semi-) quantitation of clone-specific immunoglobulin/T-cell receptor (Ig/TCR) rearrangements have documented the feasibility and practicality of this technique. This approach has also been disputed due to the occurrence of clonal evolution and generally high MRD levels prior to HSCT. PROCEDURE: In our prospective study, MRD before and after HSCT was monitored using quantitative real-time PCR in a cohort of 36 children with ALL consecutively transplanted in our center between VIII/2000 and VII/2004. RESULTS: In 25 of 36 patients, MRD level prior HSCT was assessed. Seventeen patients were classified as MRD-negative and eight were MRD-positive up to 9 x 10(-2). In MRD-positive subgroup, seven events (six relapses) occurred post-transplant in striking contrast to only one relapse in MRD-negative subgroup (event-free survival (EFS) log-rank P < 0.0001). MRD proved to be the only significant prognostic factor in a multivariate analysis (P < 0.0001). Adoptive immunotherapy including donor lymphocyte infusions in patients with adverse dynamics of MRD after HSCT had only limited and/or temporary effect. Clonal evolution did not present a problem precluding MRD monitoring in any of patients suffering a post-transplant relapse. CONCLUSIONS: We show that MRD quantitation using clonal Ig/TCR rearrangements successfully assesses the risk in pediatric ALL patients undergoing allogeneic HSCT. As our ability to treat detectable MRD levels after HSCT is very limited, alternative strategies for MRD-positive patients prior HSCT are necessary.

Adolescent↗

PubMed2006

Genetic instability and divergence of clonal populations in colon cancer cells in vitro.

The accumulation of multiple chromosomal abnormalities is a characteristic of the majority of colorectal cancers and has been attributed to an underlying chromosomal instability. Genetic instability is considered to have a key role in the generation of genetic and phenotypic heterogeneity in cancer cells. To shed light on the dynamics of chromosomal instability in colon cancer cells, we have analyzed genetic divergence in clonal and subclonal derivates of chromosomally unstable (SW480) and stable (HCT116, LoVo) cell lines. Conventional G-banding karyotyping and arbitrarily primed PCR (AP-PCR) fingerprinting were used to calculate genetic distances among clones and parental cells, and to trace tree-type phylogenies among individual cells and clonal cell populations. SW480 cells showed enhanced karyotypic heterogeneity in clones as compared with parental cells. Moreover, genetic clonal divergence was also increased after two consecutive episodes of single-cell cloning, demonstrating that the homogeneity induced by the bottleneck of cloning is disrupted by genetic instability during clonal expansion and, as a consequence, heterogeneity is restored. These results demonstrate genetic drift in clonal populations originated from isolated cells. The generated cell heterogeneity coupled with selection provides the grounds for the reported feasibility of pre-neoplastic and neoplastic cells to generate new phenotypic variants with increased evolutionary potential.

Cell Line, Tumor↗

PubMed1997

Molecular mechanisms in mitochondrial DNA depletion syndrome.

Depletion of mitochondrial DNA (mtDNA) appears to be an important cause of mitochondrial dysfunction in neonates and infants. We have identified another child in whom depletion of mtDNA was demonstrated in liver and serial skeletal muscle biopsies. A primary myoblast culture from the patient initially showed normal levels of mtDNA, but there was a progressive loss of mtDNA in later cell passages and clonal myoblast cell cultures, similar to that observed in the skeletal muscle tissue of the patient. Thus, these clonal myoblast cultures provide an in vitro model of the in vivo mtDNA dynamics. The levels of mitochondrial mRNAs for subunits I and II of cytochrome c oxidase declined with declining mtDNA levels, but the fall in mitochondrial transcript levels lagged behind that of the mtDNA levels. Levels of cytochrome c oxidase subunit I and II polypeptides, however, declined ahead of declining mtDNA levels. Immunocytochemistry showed that between individual cells of the clonal myoblast cultures, the expression of the mitochondrially encoded subunit I of cytochrome c oxidase was heterogeneous, suggesting variable levels of mtDNA. Transfer of patient mitochondria with residual mtDNA levels to control cells devoid of mtDNA (rho0 cells) led to restoration of mtDNA levels and, hence, suggests a nuclear involvement in the depletion.

Cell Nucleus↗

PubMed2006

The Bacillus cereus group: novel aspects of population structure and genome dynamics.

AIMS: To provide new insights into the population and genomic structure of the Bacillus cereus group of bacteria. METHODS AND RESULTS: The genetic relatedness among B. cereus group strains was assessed by multilocus sequence typing (MLST) using an optimized scheme based on seven chromosomal housekeeping genes. A set of 48 strains from different clinical sources was included, and six clonal complexes containing several genetically similar isolates from unrelated patients were identified. Interestingly, several clonal groups contained strains that were isolated from similar human sources. Furthermore, comparative whole genome sequence analysis of 16 strains led to the discovery of novel ubiquitous genome features of the B. cereus group, such as atypical group II introns, IStrons, and hitherto uncharacterized repeated elements. CONCLUSIONS: The B. cereus group constitutes a coherent population unified by the presence of ubiquitous and specific genetic elements which do not show any pattern, either in their sequences or genomic locations, which allows to differentiate between the member species of the group. Nevertheless, the population is very dynamic, as particular lineages of clinical origin can evolve to form clonal complexes. At the genome level, the dynamic behaviour is indicated by the presence of numerous mobile and repeated elements. SIGNIFICANCE AND IMPACT OF THE STUDY: The B. cereus group of bacteria comprises species that are of medical and economic importance. The MLST data, along with the primers and protocols used, will be available in a public, web-accessible database (http://mlstoslo.uio.no).

Bacillus cereus↗

PubMed1988

Genetic evidence for progressive selection and overgrowth of primary tumors by metastatic cell subpopulations.

We have exploited random insertions of transfected DNA as unique clonotypic markers to follow cell lineages during primary and metastatic tumor growth of a mouse mammary adenocarcinoma, SP1. Southern analysis was undertaken of primary solid tumors and metastases obtained after injection of a pooled population of individual SP1 transfectants, or reconstituted mixtures of genetically marked metastatic and unmarked nonmetastatic cells. Here we provide evidence for the reproducible selection and eventual overgrowth of primary tumors by genotypically distinct metastatic clones, thereby illustrating that late-state, advanced primary tumors can evolve to become biologically similar, or even identical, to distant metastases. The selective growth advantage of metastatic cells within primary tumors was shown to occur despite the fact that tumors generated by both metastatic and nonmetastatic SP1 cell populations grew at comparable growth rates when injected and analyzed separately. The extent of the local growth advantage manifested by individual metastatic clones varied considerably, from 5- to 50-fold. Clonal overgrowth was also observed whether the tumor cells were injected ectopically, or orthotopically (i.e., into the mammary fat). This type of experimental approach should provide new insights into the dynamics of tumor progression and metastasis, the lineage relationship of primary tumors to metastases, the influence of clonal interactions on tumor behavior, and the physiological changes which are causative of malignant disease.

Adenocarcinoma↗

PubMed1992

Structural and functional crosstalk between acetylcholine receptor and its membrane environment.

Nicotinic acetylcholine receptor (AChR) is a transmembrane protein belonging to the superfamily of rapid, ligand-operated channels. Theoretical models based on thermodynamic criteria assign portions of the polypeptide chains to the lipid bilayer region. From an experimental point of view, however, the relationship between the two moieties remains largely unexplored. Current studies from our laboratory are aimed at defining the structural, dynamic, and functional relationship between membrane lipids and AChR. We are particularly interested in establishing the characteristics of and differences between the lipids in each leaflet of the bilayer and the belt or "annular" lipids immediately surrounding AChR and the bulk bilayer lipids. We are also interested in determining the possible implications of lipid modifications on AChR channel properties. Toward these ends, fluorescence and other spectroscopic techniques, together with biochemical analyses and patch-clamp studies, are currently being undertaken. Correlations can be established between structural aspects of phospholipid packing in the immediate perimeter of AChR and other properties of these annular lipids revealed by dynamic spectroscopic and molecular modeling techniques. Lipid compositional analyses of the clonal muscle cell line BC3H-1 and chemical modification studies have been carried out by incubation of intact cells in culture and of membrane patches excised therefrom with liposomes of different lipid composition. These studies have been combined with electrophysiological measurements using the patch-clamp technique, with the aim of determining the possible effects of lipids on the channel properties of muscle-type AChR. A variety of experimental conditions, involving polar head and fatty acyl chain substitution of phospholipids and cholesterol incorporation, are being assayed in the BC3H-1 cells.

Acetylcholine↗

PubMedDate not supplied

Inhaled formaldehyde: exposure estimation, hazard characterization, and exposure-response analysis.

Formaldehyde has been assessed as a Priority Substance under the Canadian Environmental Protection Act. Probabilistic estimates of exposure of the general population in Canada to formaldehyde in ambient and indoor air are presented. Critical health effects include sensory irritation and the potential to induce tumors in the upper respiratory tract (the nasal region in rodents and potentially the lungs of humans). The majority of the general population is exposed to airborne concentrations of formaldehyde less than those typically associated with sensory irritation (i.e., 0.1 mg/m3). Based primarily upon data derived from laboratory studies, the inhalation of formaldehyde under conditions that induce cytotoxicity and sustained regenerative proliferation within the respiratory tract is considered to present a carcinogenic hazard to humans. At airborne levels for which the prevalence of sensory irritation is minimal (i.e., 0.1 mg/m3), risks of respiratory-tract cancers for the general population estimated on the basis of a biologically motivated case-specific model are exceedingly low. This biologically motivated case-specific model incorporates two-stage clonal expansion and is supported by dosimetry calculations from computational fluid dynamics analyses of formaldehyde flux in various regions of the nose and single-path modeling for the lower respiratory tract. The degree of confidence in the underlying database and uncertainties in estimates of exposure and in characterization of hazard and dose response are delineated.

Air Pollutants↗

PubMed2005

Single-cell growth and division dynamics showing epigenetic correlations.

The emergence of variation and subsequent inheritance of the emergent characteristics in a clonal population of bacteria is considered as evidence for epigenetic processes in the cell. We report here the results of experiments in which we quantitatively examined variations in single Escherichia coli cells with an identical genetic endowment in order to establish whether certain characteristics of single cells were inherited by their descendants maintained in a uniform environment. Significantly large variations of interdivision time, initial length, and final length were observed from generation to generation. Comparing the generations shows that interdivision time had no correlation with that of the consecutive generations, whereas those of initial length and final length were positively correlated with those of neighbouring generations.

Bacteriological Techniques↗

PubMed2001

Effects of Bacteriophages on the Population Dynamics of Four Strains of Pelagic Marine Bacteria.

Viral lysis of specific bacterial populations has been suggested to be an important factor for structuring marine bacterioplankton communities. In the present study, the influence of bacteriophages on the diversity and population dynamics of four marine bacterial phage-host systems was studied experimentally in continuous cultures and theoretically by a mathematical model. By use of whole genome DNA hybridization toward community DNA, we analyzed the dynamics of individual bacterial host populations in response to the addition of their specific phage in continuous cultures of mixed bacterial assemblages. In these experiments, viral lysis had only temporary effects on the dynamics and diversity of the individual bacterial host species. Following the initial lysis of sensitive host cells, growth of phage-resistant clones of the added bacteria resulted in a distribution of bacterial strains in the phage-enriched culture that was similar to that in the control culture without phages after about 50-60 h incubation. Consequently, after a time frame of 5-10 generations after lysis, it was the interspecies competition rather than viral lysis of specific bacterial strains that was the driving force in the regulation of bacterial species composition in these experiments. The clonal diversity, on the other hand, was strongly influenced by viral activity, since the clonal composition of the four species in the phage-enriched culture changed completely from phage-sensitive to phage-resistant clones. The model simulation predicted that viral lysis had a strong impact on the population dynamics, the species composition, and the clonal composition of the bacterial community over longer time scales (weeks). However, according to the model, the overall density of bacteria in the system was not affected by phages, since resistant clones complemented the fluctuations caused by viral lysis. Based on the model analysis, we therefore suggest that viral lysis can have a strong influence on the dynamics of bacterial populations in planktonic marine systems.

Journal Article↗

PubMed2006

Prey evolution on the time scale of predator-prey dynamics revealed by allele-specific quantitative PCR.

Using rotifer-algal microcosms, we tracked rapid evolution resulting from temporally changing natural selection in ecological predator-prey dynamics. We previously demonstrated that predator-prey oscillations in rotifer-algal laboratory microcosms are qualitatively altered by the presence of genetic variation within the prey. In that study, changes in algal gene frequencies were inferred from their effects on population dynamics but not observed directly. Here, we document rapid prey evolution in this system by directly observing changes in Chlorella vulgaris genotype frequencies as the abundances of these algae and their consumer, Brachionus calyciflorus, change through time. We isolated a group of algal clones that we could distinguish by using microsatellite-DNA markers, and developed an allele-specific quantitative PCR technique (AsQ-PCR) to quantify the frequencies of pairs of clones in mixed culture. We showed that two of these genotypes exhibited a fitness tradeoff in which one was more resistant to predation (more digestion-resistant), and the other had faster population growth under limiting nitrogen concentrations. A fully specified mathematical model for the rotifer-algal population and evolutionary dynamics predicted that these two clones would undergo a single oscillation in clonal frequencies followed by asymptotic fixation of the more resistant clone, rather than the recurrent oscillations previously observed with other algal clones. We used AsQ-PCR to confirm this prediction: the superior competitor dominated initially, but as rotifer densities increased, the more predator-resistant clone predominated.

Alleles↗

PubMed2025

Sustained NF-κB activation allows mutant alveolar stem cells to co-opt a regeneration program for tumor initiation.

Disruptions to regulatory signals governing stem cell fate open the pathway to tumorigenesis. To determine how these programs become destabilized, we fate-map thousands of murine wild-type and KrasG12D-mutant alveolar type II (AT2) stem cells in vivo and find evidence for two independent AT2 subpopulations marked by distinct tumorigenic capacities. By combining clonal analyses with single-cell transcriptomics, we unveil striking parallels between lung regeneration and tumorigenesis that implicate Il1r1 as a common activator of AT2 reprogramming. We show that tumor evolution proceeds through the acquisition of lineage infidelity and reversible transitions between mutant states, which, in turn, modulate wild-type AT2 dynamics. Finally, we discover how sustained nuclear factor κB (NF-κB) activation sets tumorigenesis apart from regeneration, allowing mutant cells to subvert differentiation in favor of tumor growth.

Animals↗

PubMed2025

Hidden diversity in Enterococcus faecalis revealed by CRISPR2 screening: eco-evolutionary insights into a novel subspecies.

Enterococcus faecalis is a commensal bacterium that colonizes the gut of humans and animals and is a major opportunistic pathogen, known for causing multidrug-resistant healthcare-associated infections (HAIs). Its ability to thrive in diverse environments and disseminate antimicrobial resistance genes (ARGs) across ecological niches highlights the importance of understanding its ecological, evolutionary, and epidemiological dynamics. The CRISPR2 locus has been used as a valuable marker for assessing clonality and phylogenetic relationships in E. faecalis. In this study, we identified a group of E. faecalis strains lacking CRISPR2, forming a distinct, well-supported clade. We demonstrate that this clade meets the genomic criteria for classification as a novel subspecies, here referred to as "subspecies B." Through a comprehensive pangenome analysis and comparative genomics, we explored the adaptive ecological traits underlying this diversification process, identifying clade-specific features and their predicted functional roles. Our findings suggest that the frequent isolation of subspecies B from meat products and processing facilities may reflect dissemination routes involving environmental contamination (e.g., water, plants, soil) from avian species. The absence of key virulence traits required for pathogenicity in mammals, particularly humans, and the lack of clinically relevant resistance determinants indicate that subspecies B currently poses minimal threat to public health compared with the broadly disseminated "subspecies A." Nevertheless, the unclear potential for genetic exchange between these subspecies and the frequent association of subspecies B with food sources calls for continued genomic surveillance of E. faecalis from a One Health perspective to detect and mitigate the emergence of high-risk variants in advance.IMPORTANCEExploring intraspecific genetic variability in generalist bacteria with pathogenic potential, such as Enterococcus faecalis, is a key to uncovering stable evolutionary trends. By screening the CRISPR2 locus across a representative set of genomes from diverse sources, this study reveals a previously unrecognized lineage within the population structure of E. faecalis, associated with underexplored nonhuman and nonhospital reservoirs. These findings broaden our knowledge of the species' genetic landscape and shed light on its adaptive strategies and patterns of ecological dissemination. By bridging phylogenetic patterns with variation in genetic defense systems and accessory traits, the study generates testable hypotheses about the genomic determinants and corresponding selective pressures that shape the species' behavior and long-term dissemination. This work offers new perspectives on the eco-evolutionary dynamics of E. faecalis and highlights the value of genomic surveillance beyond clinical settings, in alignment with One Health principles.

Enterococcus faecalis↗

PubMed2004

Dedifferentiated adult articular chondrocytes: a population of human multipotent primitive cells.

OBJECTIVE: To test the hypothesis that dedifferentiated adult human cartilage chondrocytes (HAC) are a true multipotent primitive population. METHODS: Studies to characterize dedifferentiated HAC included cell cycle and quiescence analysis, cell fusion, flow-FISH telomere length assays, and ABC transporter analysis. Dedifferentiated HAC were characterized by flow cytometry, in parallel with bone marrow mesenchymal stem cells (MSC) and processed lipoaspirate (PLA) cells. The in vitro differentiation potential of dedifferentiated HAC was studied by cell culture under several inducing conditions, in multiclonal and clonal cell populations. RESULTS: Long-term HAC cultures were chromosomically stable and maintained cell cycle dynamics while showing telomere shortening. The phenotype of dedifferentiated HAC was quite similar to that of human bone marrow MSC. In addition, this population expressed human embryonic stem cell markers. Multiclonal populations of dedifferentiated HAC differentiated to chondrogenic, osteogenic, adipogenic, myogenic, and neurogenic lineages. Following VEGF induction, dedifferentiated HAC expressed characteristics of endothelial cells, including AcLDL uptake. A total of 53 clonal populations of dedifferentiated HAC were efficiently expanded; 17 were able to differentiate to chondrogenic, osteogenic, and adipogenic lineages. No correlation was observed between telomere length or quiescent population and differentiation potential in the clones assayed. CONCLUSION: Dedifferentiated HAC should be considered a human multipotent primitive population.

Adipocytes↗

PubMed2005

Clonal diversity and turnover of Streptococcus mitis bv. 1 on shedding and nonshedding oral surfaces of human infants during the first year of life.

Streptococcus mitis bv. 1 is a pioneer colonizer of the human oral cavity. Studies of its population dynamics within parents and their infants and within neonates have shown extensive diversity within and between subjects. We examined the genetic diversity and clonal turnover of S. mitis bv. 1 isolated from the cheeks, tongue, and primary incisors of four infants from birth to 1 year of age. In addition, we compared the clonotypes of S. mitis bv. 1 isolated from their mothers' saliva collected in parallel to determine whether the mother was the origin of the clones colonizing her infant. Of 859 isolates obtained from the infants, 568 were unique clones. Each of the surfaces examined, whether shedding or nonshedding, displayed the same degree of diversity. Among the four infants it was rare to detect the same clone colonizing more than one surface at a given visit. There was little evidence for persistence of clones, but when clones were isolated on multiple visits they were not always found on the same surface. A similar degree of clonal diversity of S. mitis bv. 1 was observed in the mothers' saliva as in their infants' mouths. Clones common to both infant and mothers' saliva were found infrequently suggesting that this is not the origin of the infants' clones. It is unclear whether mucosal immunity exerts the environmental pressure driving the genetic diversity and clonal turnover of S. mitis bv. 1, which may be mechanisms employed by this bacterium to evade immune elimination.

Adult↗

PubMed2002

Real-time polymerase chain reaction estimation of bone marrow tumor burden using clonal immunoglobulin heavy chain gene and bcl-1/JH rearrangements in mantle cell lymphoma.

OBJECTIVE: In mantle cell lymphoma (MCL), detection of minimal residual disease in bone marrow (BM) samples by qualitative polymerase chain reaction (PCR) is insufficient to predict relapse. The aim of this study was to evaluate whether a quantitative estimation of tumor burden in consecutive BM samples from MCL patients was feasible and of clinical value. MATERIALS AND METHODS: In combination with standard qualitative PCR, we developed a sensitive and accurate real-time PCR for detection of bcl-1/JH (joining region) rearrangement and used a recently described real-time PCR analysis of clonal immunoglobulin rearrangement. To assess clinical utility, we quantified tumor cells in 27 BM samples from three MCL patients undergoing combined CHOP (cyclophosphamide, doxorubicin [hydroxydaunomycin], vincristine [Oncovin], prednisone) and anti-CD20 antibody treatment and three MCL patients undergoing up-front autologous stem cell transplantation. RESULTS: The approach is capable of detecting tumor cells over a wide range of BM contamination compared to qualitative PCR analysis alone. Tumor burden in consecutive BM samples decreases during therapy and either increases or stabilizes at low levels in patients who relapse or remain in continuous clinical remission, respectively. CONCLUSIONS: Dynamic range estimation of BM tumor burden is feasible in MCL patients undergoing therapy using clonal immunoglobulin heavy chain gene and bcl-1/JH rearrangement-based real-time PCR.

Antibodies, Monoclonal↗

PubMed2005

The evolutionary origin of genetic instability in cancer development.

The standard model of carcinogenesis is currently being questioned. The main controversy concerns genetic instability and has links to fundamental questions in evolutionary biology. This paper aims to clarify the underlying conflict between the linear configuration of the standard model and the non-linear dynamics of Darwinian evolution. It addresses the problem of applying the concept of clonal selection to genetically unstable cells and presents an alternative perspective based on the principles of molecular evolution. This model explains genetic instability in terms of competition between genetic strategies and draws lines to basic aspects of evolutionary biology.

Animals↗

PubMed1997

Mathematical models of parasite responses to host immune defences.

We examine the evolution of microparasites in response to the immune system of vertebrate hosts. We first describe a simple model for an acute infection. This model suggests that the within-host dynamics of the microparasite will be a 'race' between parasite multiplication and a clonally expanding response by the host immune system, resulting either in immune-mediated clearance or host death. In this very simple model, in which there is only a single parasite and host genotype, maximum transmission is obtained by parasites with intermediate rates of growth (and virulence). We examine how these predictions depend on key assumptions about the parasite and the host, and consider how this model may be expanded to incorporate the effect of additional complexities such as host-parasite co-evolution, host polymorphism, and multiple infections.

Animals↗