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At least 631 records · Page 35Linked to original sources
PubMed1992

Studies on protein-DNA interactions using the resonant recognition model. Application to repressors and transforming proteins.

The structural features of protein-DNA interactions have been evaluated using a new information theory algorithm for the analysis of protein structure/function dependence: the so-called resonant recognition model. The physicochemical basis of this analysis was firstly validated with the trp-repressor-operator interaction as a well-defined example. The amino acid and structural features predicted by these procedures to be crucial for repressor-operator interaction were found to be clustered around the known three-dimensional structure of the active site of the trp repressor. Similar methods of analysis have been extended to the less-well-defined example of the Ha-ras p21 protein family. The results of this analysis have indicated two distinct interactive regions in p21, one associated with the guanine-nucleotide-binding site, whilst the second is proposed to be associated with a binding site for an activator protein. These studies indicate that the p21 protein, besides the ability to function as a plasma-membrane-associated guanine-nucleotide-binding regulatory protein and bind free guanine nucleotides in the cytoplasm, has the structural ability to bind guanine incorporated in DNA. Thus, p21-related proteins may have the potential to function as an DNA-binding and regulating protein with the mode of upstream DNA binding closely related to their oncogenic function.

Animals↗
PubMed2000

Health care expenditure inertia in the OECD countries: a heterogeneous analysis.

Health care expenditure studies of the Organization for Economic Cooperation and Development (OECD) countries remain important because their findings often suggest cost containment and other policy initiatives. This paper focuses on the compatibility of OECD health data with the "expenditure inertia" (or lagged adjustments) hypothesis, by modeling individual country time-series data of 21 nations for the 1960-1993 period. Maximum likelihood estimates of the Box-Cox transformation regression models reveal that: (a) the hypothesized impact of health "expenditure inertia" is both pervasive and strong, averaging 0.64 across the countries; (b) the real GDP elasticities of health care expenditures vary widely among the countries and average 0.34 in the short run--implying that health care is a necessity; (c) the long run GDP elasticities are less than 1 in 8 countries, unitary elastic in 8 countries and elastic in 5 countries--suggesting that health care is not universally a necessity or a luxury commodity for the OECD countries; (d) physician-inducement effects (dis-inducement in a few countries) are weak, with a mean elasticity estimate of 0.17; and (e) no unique functional form approximation model is globally compatible with the data across the countries. Health care cost containment policy implications of these findings are explored.

Benchmarking↗
PubMed1975

Transformation and transfection in lysogenic strains of Bacillus subtilis: evidence for selective induction of prophage in competent cells.

Lysogenic strains of Bacillus subtilis 168 were reduced in their level of transformation as compared to non-lysogenic strains. The level of transformation decreased even further if the competent lysogenic cells were allowed to incubate in growth media prior to selection on minimal agar. This reduction in the frequency of transformation was attributable to the selective elimination of transformed lysogenic cells from the competent population. Concurrent with the decrease in the number of transformants from a lysogenic competent population was the release of bacteriophage by these cells. The lysogenic bacteria demonstrated this dramatic release of bacteriophage only if the cells were grown to competence. Both the selective elimination of transformed lysogens and the induction of prophage was prevented by the inhibition of protein synthesis. Additionally, competent lysogenic cells released significantly higher amounts of exogenous donor transforming deoxyribonucleic acid than did competent non-lysogenic cells or competent lysogenic cells incubated with erythromycin. These data establish that the induction of the prophage from the competent lysogenic cells was responsible for the selective elmination of the lysogenic transformants. A model is presented that accounts for the induction of the prophage from competent lysogenic bacteria via the induction of a repair system. It is postulated that a repair system is induced or derepressed by the accumulation of gaps in the chromosomes of competent bacteria. This hypothetical enzyme(s) is ultimately responsible for the induction of the prophage and the selective elimination of transformants.

Azo Compounds↗
PubMed1992

Structural identifiability of the parameters of a nonlinear batch reactor model.

The similarity transformation approach is used to analyze the structural identifiability of the parameters of a nonlinear model of microbial growth in a batch reactor in which only the concentration of microorganisms is measured. It is found that some of the model parameters are unidentifiable from this experiment, thus providing the first example of a real-life nonlinear model that turns out not to be globally identifiable. If it is possible to measure the initial concentration of growth-limiting substrate as well, all model parameters are globally identifiable.

Bacteria↗
PubMed1998

A requirement for NF-kappaB activation in Bcr-Abl-mediated transformation.

Bcr-Abl is a chimeric oncoprotein that is strongly implicated in acute lymphoblastic (ALL) and chronic myelogenous leukemias (CML). This deregulated tyrosine kinase selectively causes hematopoietic disorders resembling human leukemias in animal models and transforms fibroblasts and hematopoietic cells in culture. Bcr-Abl also protects cells from death induced on cytokine deprivation or exposure to DNA damaging agents. In addition, the antiapoptotic function of Bcr-Abl is thought to play a necessary role in hematopoietic transformation and potentially in leukemogenesis. The transcription factor NF-kappaB has been identified recently as an inhibitor of apoptosis and as a potential regulator of cellular transformation. This study shows that expression of Bcr-Abl leads to activation of NF-kappaB-dependent transcription by causing nuclear translocation of NF-kappaB as well as by increasing the transactivation function of the RelA/p65 subunit of NF-kappaB. Importantly, this activation is dependent on the tyrosine kinase activity of Bcr-Abl and partially requires Ras. The ability of Bcr-Abl to protect cytokine-dependent 32D myeloid cells from death induced by cytokine deprivation or DNA damage does not, however, require functional NF-kappaB. However, using a super-repressor form of IkappaBalpha, we show that NF-kappaB is required for Bcr-Abl-mediated tumorigenicity in nude mice and for transformation of primary bone marrow cells. This study implicates NF-kappaB as an important component of Bcr-Abl signaling. NF-kappaB-regulated genes, therefore, likely play a role in transformation by Bcr-Abl and thus in Bcr-Abl-associated human leukemias.

Animals↗
PubMed2001

MRI of subacute hemorrhagic transformation in the rat suture occlusion model.

In this study we investigated the utility of different MRI techniques for the detection and predictability of hemorrhagic transformation (HT) in a rat model of transient focal cerebral ischemia. Hemorrhagic infarction was reliably identified with gradient-echo sequences and developed between 2 and 7 days following the insult. None of the investigated early MRI features of the ischemic lesions (including the apparent diffusion coefficient and post-reperfusion blood-brain barrier damage) was a good predictor of HT severity at 7 days. This indicates that subacute HT at 2-7 days occurs independently of the severity of acute tissue and BBB damage.

Acute Disease↗
PubMed1995

Malignant transformation of the liver tumour precursor cell line OC/CDE 22 by the four stereoisomeric fjord region 3,4-dihydrodiol 1,2-epoxides of benzo[c]phenanthrene.

In previous work we established the rat liver oval cell line OC/CDE 22 in order to study in vitro mechanisms of liver cell transformation. We have now exposed OC/CDE 22 cells to each of the four optically active fjord region dihydrodiol epoxides of benzo[c]phenanthrene to investigate their capacity for malignant transformation of liver cells. All four configurational isomers, which are among the most potent carcinogenic metabolites of polycyclic aromatic hydrocarbons tested in murine tumour models, malignantly transform OC/CDE 22 cells at a 2 microM dose level, resulting in a similar colony-forming efficiency in soft agar. Inoculation of the transformed cells into newborn syngeneic rats produced an extremely high incidence of carcinomas with a short latency period. The induced carcinomas displayed cholangiocellular, adenoid and solid growing structures. Neither cell growth in soft agar nor induction of tumor formation in newborn rats were achieved if confluent OC/CDE 22 cell cultures were exposed to each of the four stereoisomers and left in the confluent state for 4 weeks. In contrast, if confluent cells were exposed to the four stereoisomers, immediately split and then subcultured as usual, full transformation was accomplished. Our results indicate that the fjord region dihydrodiol epoxides of benzo[c]phenanthrene are highly efficient transforming agents for rat liver cells and that proliferation plays a pivotal role in the liver cell transformation process induced by polycylic aromatic hydrocarbons.

Animals↗
PubMedDate not supplied

Quantitative prediction of biodegradability, metabolite distribution and toxicity of stable metabolites.

An evaluation of the capability of organic chemicals to mineralize is an important factor to consider when assessing their fate in the environment. Microbial degradation can convert a toxic chemical into an innocuous one, and vice versa, or alter the toxicity of a chemical. Moreover, primary biodegradation can convert chemicals into stable products that can be difficult to mineralize. In this paper, we present some new results obtained on the basis of a recently developed probabilistic approach to modeling biodegradation based on microbial transformation pathways. The metabolic transformations and their hierarchy were calibrated by making use of the ready biodegradability data from the MITI-I test and expert knowledge for the most probable transformation pathways. A model was developed and integrated into an expert software system named CATABOL that is able to predict the probability of biodegradation of organic chemicals directly from their structure. CATABOL simulates the effects of microbial enzyme systems, generates the most plausible transformation pathways, and quantitatively predicts the persistence and toxicity of the biodegradation products. A subset of 300 organic chemicals were selected from Canada's Domestic Substances List and subjected to CATABOL to compare predicted properties of the parent chemicals with their respective first stable metabolite. The results show that most of the stable metabolites have a lower acute toxicity to fish and a lower bioaccumulation potential compared to the parent chemicals. In contrast, the metabolites appear to be generally more estrogenic than the parent chemicals.

Animals↗
PubMed2005

A stem cell fusion model of carcinogenesis.

The origin of cancer remains enigmatic. Current models of carcinogenesis based on the gene mutation hypothesis have limitations in explaining many aspects of cancer. We put forward a new model of multistage carcinogenesis and propose that cancer development involves gene mutations and cell fusions. Specifically, cancer can result from a fusion between an "altered" pre-malignant cell and a bone marrow-derived stem cell (BMDSC). "Aneuploidy", which is a hallmark of malignancy, is a direct consequence of this cell fusion. The "stem cell fusion" model explains the remarkable similarities between malignant cells and BMDSC. This model also explains why non-mutagens can be carcinogens, and why non-mutagenic processes, such as wound healing and chronic inflammation, can promote malignant transformation. This model is readily testable. Cancer has been difficult to treat because of tissue heterogeneity and gene instability. However, if the malignant characteristics of cancer cells are derived from BMDSC, new conserved targets such as homing receptors for designing novel therapies may emerge.

Aging↗
PubMed1991

A plausible model for reversal of neoplastic transformations in plants based on multiple steady states.

We offer a plausible interpretation of some experiments on the reversal of neoplastic transformations in plants. We suggest that normal cells and tumorous cells represent multiple stable-steady states corresponding to a reaction feedback mechanism. The (autocatalytic) feedback loop is constructed from observations on the role played by myo-inositol: it increases the permeability of ions through the membrane and the biosynthetic pathway to myo-inositol is activated by ions. Provided that the permeabilities of nutrients (sugars and salts) are a product-enhanced function of myo-inositol, then we have a (oversimplified) model that can exhibit multiple stationary stable states, one or two depending on the exogenous nutrients and myo-inositol concentrations, and reversible and irreversible transitions from one of these states to the other are possible. From this model, straightforward simple experiments are suggested. We also propose that recent models dealing with the intracellular calcium regulation by hormones, where one key step requires the hydrolysis of inositol phospholipids, take into account free myo-inositol and endogenous hormone concentrations (e.g., auxins).

Calcium↗
PubMed2002

A model of accelerated aging induced by 5-bromodeoxyuridine.

We consider a scheme of aging with two possible mechanisms of senescence processes: aging with apoptosis and necrosis for differentiated cells and a multistage process of malignant transformation. Our model describes the multistage phenomena of aging and carcinogenesis by a set of stochastic equations using multivariate and diffusion processes. This model fits experimental data on the acceleration of aging processes from postnatal exposure to 5-bromodeoxyuridine (BrdU), and the induction of genome instability. The methods of stochastic modeling and computer simulation of the processes of aging and carcinogenesis have been used for the verification of the biological suggestions.

Aging↗
PubMed2004

Nkx2.1 transcription factor in lung cells and a transforming growth factor-beta1 heterozygous mouse model of lung carcinogenesis.

The Nkx2.1 homeobox gene and transforming growth factor-beta1 (TGF-beta1) are essential for organogenesis and differentiation of the mouse lung. NKX2.1 is a marker of human lung carcinomas, but it is not known whether this gene participates in early tumorigenesis. Addition of TGF-beta1 to TGF-beta1-responsive nontumorigenic mouse lung cells cotransfected with a NKX2.1Luc luciferase reporter and either a Sp1 or Sp3 plasmid showed a significant increase or decrease, respectively, in NKX2.1Luc transcription. Cotransfection of Sp3 and dominant-negative TGF-beta type II receptor plasmids negated the effect of Sp1. Cotransfected Sp1 plasmid with either dominant-negative Smad2 or Smad3 or Smad4 plasmids significantly decreased NKX2.1Luc transcription. Electrophoretic mobility shift assays revealed binding of Sp1 and Smad4 to the NKX2.1 promoter. With a TGF-beta1 heterozygous mouse model, Nkx2.1 mRNA and protein in lungs of TGF-beta1 heterozygous mice were significantly lower compared to wildtype (WT) littermates. Competitive reverse transcription (RT)-polymerase chain reaction (PCR) and immunostaining showed that Nkx2.1 mRNA and protein decreased significantly in adenomas and adenocarcinomas compared to normal lung tissue. Our in vitro data showed that regulation of Nkx2.1 by TGF-beta1 occurs through TGF-beta type II receptor and Smad signaling, with Sp1 and Sp3 in lung cells. Our in vivo data showed reduced Nkx2.1 in lungs of TGF-beta1 heterozygous mice compared to WT mice, that is detectable in adenomas, and that is further reduced in carcinogenesis, and that correlates with reduction of Sp1, Sp3, and Smads in lung adenocarcinomas. Our findings suggest that reduced Nkx2.1 and TGF-beta1 signaling components may contribute to tumorigenesis in the lungs of TGF-beta1 heterozygous mice.

Animals↗
PubMed2005

Estimating the global order of the fMRI noise model.

One of the major issues in GLM-based fMRI analysis techniques is the presence of temporal autocorrelations in the residual signal after regression. A possible correction method is that of prewhitening, which fits an autoregressive (or other) model to the residual and uses the expected temporal autocorrelations of the model to transform the data and design matrix such that the residual becomes white noise. In this article, a method is introduced to estimate the global autoregressive model order of a data set, based on the residuals after regression. The proposed global standardized partial autocorrelation (SPAC) method tests whether the spatial profile of partial autocorrelations at a certain lag is random, and uses random field theory to account for the spatial correlations typical for fMRI data. It is tested both on synthetic and fMRI data, and is compared to two traditional techniques for model order estimation.

Algorithms↗
PubMed2004

Sacred changes: Spiritual conversion and transformation.

We use Pargament's (1997) definition of religion-"the search for significance in ways related to the sacred"-as a framework to understand spiritual conversion. Like other life-changing transformations, spiritual conversion alters the destinations that clients perceive to be of greatest importance in life (significance) and the pathways by which clients discover what is most significant in life (search). Unlike other transformative experiences, however, spiritual conversion incorporates the third element of religion, "the sacred," into the content of change. To illustrate these points, we discuss two theological models of spiritual conversion rooted in Christianity: a traditional model based on classic western theology and an alternative model based on feminist theology. We then compare processes of spiritual conversion to nonreligious models of transformation. We also highlight the importance for clinical work of the fit between the context of a client's life and the type of spiritual conversion experienced.

Christianity↗
PubMed1998

[Lymphocyte transformation test (LTT) as a model for evaluating cytokine-induced immunomodulation in renal cell carcinoma].

We investigated the immunomodulatory capacity of cytokines produced by renal cell carcinoma in vitro by analyzing their effects on mitogen-induced T-lymphocyte blast cell transformation. All of the tested 70 cell cultures, derived from 70 tumor areas in 33 patients, had immunomodulatory capacity. In addition to suppression in the lymphocyte transformation test (max. 44/70; 63%) there was also superinduction (max. 37/70; 53%). We found no significant correlation with the stage and grade of primary tumors. However, the suppression of mitogen-induced T-lymphocyte blast cell transformation was significant in multifocal tumors (0.08% TCM, P < 0.001) and non-significant in metastatic tumors. The production of the assayed cytokines IL-6, IL-10, IL-11, and TGF beta 1 was variable and there was no significant correlation to the immunomodulatory capacity of the tumors.

Carcinoma, Renal Cell↗
PubMed2005

Modelling of mercury transport and transformation processes in the Idrijca and Soca river system.

In the town of Idrija, Slovenia, the world's second largest mercury mine was active for 500 years and about 37,000 tons of mercury has been lost in the environment. Mercury is still drained from soil, riverbed and floodplains and transported with the Idrijca and Soca Rivers to the Gulf of Trieste. A part of inorganic mercury is methylated either in the river system, or later in the coastal area, and, due to its bioaccumulation and biomagnification represents potential danger to human health. A 1-D aquatic model MeRiMod was used to simulate hydrodynamics and sediment transport in the river system from Idrija to the Soca River mouth. Transport of particle bound and dissolved mercury as well as potential net methylation of mercury in the river system was simulated. The simulation of an observed flood wave with 20-year recurrence period was performed in order to validate the model. Methylation was simulated at lower discharges, as higher methylation rates occur in such conditions. The measurement data and the MeRiMod model were also used to establish a historical mercury mass balance of the Idrijca and Soca Rivers catchment. Sediment core data from the Gulf of Trieste and the measured concentrations from floodplains were used to verify and calibrate the model. Simulations of different high discharges were performed as most of the transport of particulate mercury occurs within flood wave conditions. Compared to the measurements, the results of the model showed an agreement within an order of magnitude, for the transport of total mercury mostly within a factor of 4, and for the methylation within a factor of 5. However, proper trends of the phenomena were obtained by simulations. The combination of modelling and measurements has resulted in some interesting conclusions about the phenomenon of the transport and transformations of mercury in the observed river system.

Mercury↗
PubMed1983

Impaired spreading of transformed cells on fibrin substrate.

Fibroblast-like cells derived from C3H mice at the first passage in culture, and a line from the same origin, which had undergone spontaneous transformation at the eleventh passage, were seeded on fibrin plates and tested for their attachment and spreading. After 4-24 hours normal cells had a spider-like morphology, while transformed cells remained in round clusters, flattened on the substrate. This data represent the morphological counterpart of the abnormal fibroblast-fibrin interaction shown in a tridimensional model, where transformed cells were found unable to induce the retraction of a fibrin clot (FCR).

Animals↗