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PubMed2005

erbB-2/neu transformed rat cholangiocytes recapitulate key cellular and molecular features of human bile duct cancer.

BACKGROUND & AIMS: Cholangiocarcinomas appear to arise from the malignant transformation of cholangiocytes lining the biliary tract. Because the development of an in vitro model of malignant transformation can provide a powerful new tool for establishing critical events governing the molecular pathogenesis of cholangiocarcinoma, we investigated the potential of achieving malignant transformation of cultured rat cholangiocytes in relation to aberrant overexpression of mutationally activated erbB-2/neu. METHODS: Malignant neoplastic transformation was achieved after infection of the rat cholangiocyte cell line, designated BDE1, with the retrovirus Glu664-neu, containing the transforming rat erbB-2/neu oncogene. RESULTS: Compared with untransformed control cells, malignant transformants carrying the activating erbB-2/neu mutation prominently overexpressed p185neu receptor protein, which was phosphorylated strongly at its major autophosphorylation site at tyrosine 1248. Moreover, erbB-2/neu transformation of BDE1 cells resulted in increased telomerase activity, up-regulation of cyclooxygenase-2 with overproduction of prostaglandin E(2), enhanced phosphorylation of mitogen-activated protein kinase and of serine/threonine kinase Akt/PKB, overexpression of vascular endothelial growth factor, and increased mucin 1 messenger RNA expression. Only erbB-2/neu transformants were tumorigenic when transplanted into isogeneic rats, yielding a 100% incidence of tumors closely resembling human desmoplastic ductal cholangiocarcinomas in their morphology. Malignant cholangiocytes in the tumors were strongly immunoreactive for biliary cytokeratin 19, p185neu, and cyclooxygenase-2. CONCLUSIONS: This unique malignant transformation model recapitulates key molecular features of the human disease and appears to be well suited for testing novel molecular therapeutic strategies against cholangiocarcinoma.

Animals↗
PubMedDate not supplied

Identification, display, and use of symmetry elements in atomic and electronic structure models.

Crystallographic symmetry plays an important role in structure determination from diffraction or scattering data, in spectroscopy and in simulations. It is convenient and insightful to integrate the display and use of such symmetry data with data analysis and modeling methods. We outline the integration of a suite of crystallographic algorithms, closely coupled with interactive graphical displays. These include techniques for identifying the unit cell of a solid, for automatically determining space and point group symmetries, for generalized displays of symmetry elements overlaid on structural models, and for construction, editing, and transformation of models subject to symmetry constraints. In addition, electron densities derived from periodic density functional calculations can be symmetrized and displayed with the corresponding symmetry elements. Applications of these various capabilities in crystallographic research are illustrated by topical examples.

Aluminum Oxide↗
PubMed1980

Mapping of transforming region of the Harvey murine sarcoma virus genome by using insertion-deletion mutants constructed in vitro.

Circular DNA intermediates of Harvey murine sarcoma virus (Ha-MuSV) have been cloned in lambda gtWES . lambda B and shown to be capable of transforming mouse NIH 3T3 cells [Hager, G. L., Chang, E. H., Chan, H. W., Garon, C. F., Israel, M. A., Martin, M. A., Scolnick, E. M. & Lowy, D. R. (1979) J. Virol. 31, 795-809]. By using the cloned Ha-MuSV DNA insert as a parental genome, we have constructed a series of insertion-deletion mutants by inserting an octomer containing the Sal I linker sequence (G-G-T-C-G-A-C-C) into various regions of the Ha-MuSV genome after partial digestion with Hae III. After ligation into lambda gtWES . lambda B-Sal I vector molecules, the mutant Ha-MuSV DNAs were cloned. Fourteen insertion-deletion mutants have been mapped by restriction enzyme digestion, and their biological activities have been correlated with the locations of mutations. The mutants whose lesion mapped within 3.0 kilobases (kb) frm the 3'-end of the Ha-MuSV genome retained full transforming ability. The mutants containing the Sal I linker insertion at 0.4 or 1.5 kb from the 5'-end also retained transforming ability, but the number of foci induced by the DNAs in transfection assays was greatly reduced. However, a mutant containing a deletion of 1.5 kb at the 5'-end and a mutant with a deletion of the sequences between 1.0 and 1.5 kb from the 5'-end completely lost their transforming potential. A model for the transforming region of Ha-MuSV is discussed. Furthermore, because Ha-MuSV sequences can be rescued from the mouse cells transformed by these mutants using Moloney murine leukemia virus as a helper virus, it implies that the in vitro modified DNAs may be converted into genuine mutant viruses.

Cell Transformation, Viral↗
PubMedDate not supplied

Automated diagnosis of data-model conflicts using metadata.

The authors describe a methodology for helping computational biologists diagnose discrepancies they encounter between experimental data and the predictions of scientific models. The authors call these discrepancies data-model conflicts. They have built a prototype system to help scientists resolve these conflicts in a more systematic, evidence-based manner. In computational biology, data-model conflicts are the result of complex computations in which data and models are transformed and evaluated. Increasingly, the data, models, and tools employed in these computations come from diverse and distributed resources, contributing to a widening gap between the scientist and the original context in which these resources were produced. This contextual rift can contribute to the misuse of scientific data or tools and amplifies the problem of diagnosing data-model conflicts. The authors' hypothesis is that systematic collection of metadata about a computational process can help bridge the contextual rift and provide information for supporting automated diagnosis of these conflicts. The methodology involves three major steps. First, the authors decompose the data-model evaluation process into abstract functional components. Next, they use this process decomposition to enumerate the possible causes of the data-model conflict and direct the acquisition of diagnostically relevant metadata. Finally, they use evidence statically and dynamically generated from the metadata collected to identify the most likely causes of the given conflict. They describe how these methods are implemented in a knowledge-based system called GRENDEL and show how GRENDEL can be used to help diagnose conflicts between experimental data and computationally built structural models of the 30S ribosomal subunit.

Algorithms↗
PubMed2002

Prediction of stroke in the general population in Europe (EUROSTROKE): Is there a role for fibrinogen and electrocardiography?

BACKGROUND: To decide whether a person with certain characteristics should be given any kind of intervention to prevent a cardiovascular event, it would be helpful to classify subjects in low, medium and high risk categories. The study evaluated which well known cerebrovascular and cardiovascular correlates, in particular fibrinogen level and ECG characteristics, are able to predict the occurrence of stroke in men of the general population using data from three European cohorts participating in EUROSTROKE. METHODS: EUROSTROKE is a collaborative project among ongoing European population based cohort studies and designed as a prospective nested case-control study. For each stroke case two controls were sampled. Strokes were classified according to MONICA criteria or reviewed by a panel of four neurologists. Complete data were available of 698 men (219 stroke events) from cohorts in Cardiff (84 cases/200 controls), Kuopio (74/148) and Rotterdam (61/131). Multivariable logistic regression modeling was used to evaluate which information from history, physical examination (for example, blood pressure), blood lipids, and fibrinogen and ECG measurements independently contributed to the prediction of stroke. The area under receiver operating characteristic curve (ROC area) was used to estimate the predictive ability of models. RESULTS: Independent predictors from medical history and physical examination were age, stroke history, medically treated hypertension, smoking, diabetes mellitus and diastolic blood pressure. The ROC area of this model was 0.69. After validating and transforming this model to an easy applicable rule, 40% of all future stroke cases could be predicted. Adding pulse rate, body mass index, blood lipids, fibrinogen level and ECG parameters did not improve the classification of subjects in low, medium and high risk. Results were similar when fibrinogen was dichotomised at the upper tertile or quintile. CONCLUSION: In the general male population the future occurrence of stroke may be predicted using easy obtainable information from medical history and physical examination. Measurement of pulse rate, body mass index, blood lipids, fibrinogen level and ECG characteristics do not contribute to the risk stratification of stroke and have no value in the screening for stroke in the general male population.

Adult↗
PubMed1990

Epidermal cell-shape regulation and subpopulation kinetics during butyrate-induced terminal maturation of normal and SV40-transformed human keratinocytes: epithelial models of differentiation therapy.

Recent data indicate that malignant human epidermal cells may be appropriate targets for sodium butyrate (NaB)-mediated differentiation therapy. The response of pre- and post-crisis populations of SV40-transformed human keratinocytes (SVKs) to this differentiation-inducing agent was assessed, therefore, within the framework of NaB-directed normal human keratinocyte (NHK) maturation. NaB augmented cornified envelope (CE) production in NHK and pre-crisis SVK cultures; the time-course and efficiency of induced maturation were similar in the 2 cell systems. In NHKs, the percentage of amplifying ("B" substate) cells decreased with time in NaB correlating with increases in both "C" stage keratinocytes and CEs. The latter formed over one or 2 layers of nucleated basal-like cells. Inductions were accompanied by immediate cell cycle blocks (in both the G1 and G2/M phases), reorganization within the actin cytoskeleton, and transient early increases in cellular actin content. Increased NHK and pre-crisis SVK cytoskeletal-associated actin reached a maximum approximately 48 hr after NaB addition and preceded development of CEs. The CE precursors, thus, probably reside in the "B" substate. Post-crisis SVKs, in contrast, were refractive to NaB-induced terminal maturation or cell-cycle perturbation, failed to initiate actin filament rearrangements, and retained a basal cell-like phenotype. Stable transformation of human SVKs in post-crisis phase, therefore, appears to be associated with loss of maturation "competence" within the "B" keratinocyte subpopulation.

Actin Cytoskeleton↗
PubMed1999

An active-medium model of organic substance transformation in soil and its dynamic properties.

An analysis of the behaviour of the soil system considered as an active medium with distributed energy sources was undertaken. This approach enabled the authors to build a heuristic model of soil which accounts for processes of organic substance production, migration and utilisation. The soil body is presented as a spatially distributed trophic chain with non-linear interactions of adjacent links. The level of this non-linearity appears to be the key parameter determining the dynamic behaviour of the model system in one-, two- and three-dimensional cases. The conditions for the existence of pulse-generating and autowave modes in this system were determined by computer simulations. Of particular interest is the behaviour of damaged soil, especially its self-regeneration potential. Inoculation autowave was proven to restore the initial state of the soil if two adjacent or separated trophic links fall out. Possible ways of the further development of the proposed model are also discussed.

Models, Biological↗
PubMed2005

A model wheat cultivar for transformation to improve resistance to Fusarium Head Blight.

Fusarium head blight (FHB), caused primarily by Fusarium graminearum, is a major disease problem in wheat (Triticum aestivum). Genetic engineering holds significant potential to enhance FHB resistance in wheat. Due to the requirement of screening for FHB resistance on flowers at anthesis, the number of screens carried out in a year is limited. Our objective was to evaluate the feasibility of using the rapid-maturing dwarf wheat cultivar Apogee as an alternative genotype for transgenic FHB resistance research. Our transformation efficiency (number of transgenic plants/number of embryos) for Apogee was 1.33%. Apogee was also found to exhibit high FHB susceptibility and reached anthesis within 4 weeks. Interestingly, microsatellite marker haplotype analysis of the chromosome 3BS FHB resistant quantitative trait locus (QTL) region indicated that this region maybe deleted in Apogee. Our results indicate that Apogee is particularly well suited for accelerating transgenic FHB resistance research and transgenic wheat research in general.

Fusarium↗
PubMed1993

A computational model of echo processing and acoustic imaging in frequency-modulated echolocating bats: the spectrogram correlation and transformation receiver.

The spectrogram correlation and transformation (SCAT) model of the sonar receiver in the big brown bat (Eptesicus fuscus) consists of a cochlear component for encoding the bat's frequency modulated (FM) sonar transmissions and multiple FM echoes in a spectrogram format, followed by two parallel pathways for processing temporal and spectral information in sonar echoes to reconstruct the absolute range and fine range structure of multiple targets from echo spectrograms. The outputs of computations taking place along these parallel pathways converge to be displayed along a computed image dimension of echo delay or target range. The resulting image depicts the location of various reflecting sources in different targets along the range axis. This series of transforms is equivalent to simultaneous, parallel forward and inverse transforms on sonar echoes, yielding the impulse responses of targets by deconvolution of the spectrograms. The performance of the model accurately reproduces the images perceived by Eptesicus in a variety of behavioral experiments on two-glint resolution in range, echo phase sensitivity, amplitude-latency trading of range estimates, dissociation of time- and frequency-domain image components, and ranging accuracy in noise.

Animals↗
PubMed2001

Nitrogen transformations in a wetland receiving lagoon effluent: sequential model and implications for water reuse.

Constructed wetlands could be components of low-tech systems to treat and reuse wastewater in arid region. A key function of the wetland would be to provide additional N removal. To improve design criteria, a sequential model of nitrogen transformations (organic N --> ammonium: ammonium --> nitrate: nitrate --> nitrogen gas) was successfully calibrated and verified for a wetland in Kingman, Arizona. A sequential model has the ability to "recognize" species of nitrogen in the influent and predict species of nitrogen in the effluent. Model scenarios show that increasing nitrification rates in the summer and denitrification rates in the winter would improve nitrogen removal efficiencies. Several lines of evidence suggest that wintertime denitrification may be limited by carbon supply. Winter carbon supply could be augmented by routing a portion of the water through channels planted with dryland vegetation.

Carbon↗
PubMed1999

Series analyses and quality specifications required for monitoring over time.

General specifications of analytical goals for biochemical monitoring have been proposed based on biological within-subject variation. As a complement to this strategy for general global quality requirements there is also a need for other methods and approaches to set more optimal requirements in specific monitoring situations, i.e. application of systems and sensitivity analysis using (i) rules for propagation of errors (uncertainty) in simple algebraic/statistical transformations of laboratory results; (ii) biochemical/pathophysiological simulation models; and (iii) formalized descriptions of clinical classification and decision support processes. The possible gain in medical outcome by improving analytical and preanalytical quality should then be related to the often more important aspects of selection and combination of "tests", period and frequency of sampling/measurement, and the use of correct conceptual and computational models for transformation of data.

Clinical Laboratory Techniques↗
PubMedDate not supplied

Modeling carbon and nitrogen transformations for adjustment of compost application with nitrogen uptake by wheat.

Environmentally sound management of the use of composts in agriculture relies on matching the rate of release of available N from compost-amended soils to the crop demand. To develop such management it is necessary to (i) characterize the properties of composts that control their rates of decomposition and release of N and (ii) determine the optimal amount of composts that should be applied annually to wheat (Triticum aestivum L.). Carbon and N mineralization were measured under controlled conditions to determine compost decomposition rate parameters, and the NCSOIL model was used to derive the organic wastes parameters that control the rates of N and C transformations in the soil. We also characterized the effect of a drying period to estimate the effects of the dry season on C and N dynamics in the soil. The optimized compost parameters were then used to predict mineral N concentration dynamics in a soil-wheat system after successive annual applications of compost. Sewage sludge compost (SSC) and cattle manure compost (CMC) mineralization characteristics showed similar partitioning into two components of differing ease of decomposition. The labile component accounted for 16 to 20% of total C and 11 to 14% of total N, and it decomposed at a rate of 2.4 x 10(-2) d(-1), whereas the resistant pool had a decomposition rate constant of 1.2 to 1.4 x 10(-4) d(-1). The main differences between the two composts resulted from their total C and N and inorganic N contents, which were determined analytically. The long-term effect of a drying period on C and N mineralization was negligible. Use of these optimization results in a simulation of compost mineralization under a wheat crop, with a modified plant-effect version of the NCSOIL model, enabled us to evaluate the effects of the following factors on the C and N dynamics in soil: (i) soil temperature, (ii) mineral N uptake by plants, and (iii) release of very labile organic C in root exudates. This labile organic C enhanced N immobilization following application, and so decreased the N available for uptake by plants.

Agriculture↗
PubMed2006

The sigmoidally transformed cosine curve: a mathematical model for circadian rhythms with symmetric non-sinusoidal shapes.

We introduce a family of non-linear transformations of the traditional cosine curve used in the modelling of biological rhythms. The non-linear transformation is the sigmoidal family, represented here by three family members: the Hill function, the anti-logistic function, and the arctangent function. These transforms add two additional parameters that must be estimated, in addition to the acrophase, MESOR, and amplitude (and period in some applications), but the estimated curves have shapes requiring many more than two additional harmonics to achieve the same fit when modelled by harmonic regression. Particular values of the additional parameters can yield rectangular waves, narrow pulses, wide pulses, and for rectangular waves (representing alternating 'on' and 'off' states) the times of onset and offset (hence duration, as when modelling the duration of the large night-time melatonin secretory epoch). We illustrate the sigmoidally transformed cosine curves, and compare them to harmonic regression modelling, in a sample of eight activity recordings made on patients in a nursing home.

Aged↗
PubMed2001

The bystander effect in radiation oncogenesis: II. A quantitative model.

There is strong evidence that biological response to ionizing radiation has a contribution from unirradiated "bystander" cells that respond to signals emitted by irradiated cells. We discuss here an approach incorporating a radiobiological bystander response, superimposed on a direct response due to direct energy deposition in cell nuclei. A quantitative model based on this approach is described for alpha-particle-induced in vitro oncogenic transformation. The model postulates that the oncogenic bystander response is a binary "all or nothing" phenomenon in a small sensitive subpopulation of cells, and that cells from this sensitive subpopulation are also very sensitive to direct hits from alpha particles, generally resulting in a directly hit sensitive cell being inactivated. The model is applied to recent data on in vitro oncogenic transformation produced by broad-beam or microbeam alpha-particle irradiation. Two parameters are used in analyzing the data for transformation frequency. The analysis suggests that, at least for alpha-particle-induced oncogenic transformation, bystander effects are important only at small doses-here below about 0.2 Gy. At still lower doses, bystander effects may dominate the overall response, possibly leading to an underestimation of low-dose risks extrapolated from intermediate doses, where direct effects dominate.

Apoptosis↗
PubMed2002

Simulating and testing visual exploration in spatial neglect based on a new model for cortical coordinate transformation.

Most studies of object and space perception have focused on neural representations of either object-centered or egocentric coordinate systems. But daily life requires interactions of both kinds of coordinates. We have recently proposed an 'integrated space-object (ISO-) map' combining both coordinate systems in one representation. Based on a lesioned version of this model, here we present results from visual search simulations demonstrating that the model accounts for contralesional neglect during space-centered and object-centered exploration tasks. Interestingly, the model simulations also predicted an amelioration of neglect symptoms during exploration with more ipsilesional object positions. By measuring the eye movements of neglect patients during different exploratory tasks, we confirmed all model predictions. These results corroborate the view that the brain might combine coordinates for object and space perception in an integrated coordinate system as suggested by the ISO-map model.

Aged↗
PubMed2005

Comparison of the autoregressive modeling and fast Fourier transformation in demonstrating Doppler spectral waveform changes in the early phase of atherosclerosis.

In this study, we have performed fast Fourier transformation (FFT) and autoregressive (AR) signal processing of the Doppler signals at a nonstenotic arterial site in patients with atherosclerosis and healthy volunteers. We have not only utilized Doppler sonograms, but also facilitated the power spectral density distribution graphs using AR modeling and FFT. Our preliminary analysis show that AR modeling has a higher efficacy in demonstrating Doppler spectral waveform changes in the preclinic or silent phase of atherosclerosis. AR has especially revealed an outstanding difference in the calculation for frequency level of maximum power spectral density.

Adult↗