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At least 73 records · Page 4Linked to original sources
PubMed2005

Experimental manipulation of transforming growth factor-beta isoforms significantly affects adhesion formation in a murine surgical model.

Transforming growth factor-beta (TGF-beta), a multifunctional growth factor, represents three mammalian isoforms, TGF-beta1, TGF-beta2, and TGF-beta3. In cutaneous wound healing, combined neutralization of TGF-beta1 and -beta2 or addition of TGF-beta3 reduces scar formation. Here, we investigated whether experimental manipulation of TGF-beta isoforms reduced adhesion formation after injury to the peritoneum. Adhesions were produced in mice by surgical abrasion of adjacent serosa followed by close apposition. In the first part of this study, a detailed analysis of TGF-beta isoform distribution was performed through immunolocalization. TGF-beta isoforms clearly showed a unique temporal and spatial pattern of expression after peritoneal wounding. Based on this pharmacokinetic data, we next administered neutralizing antibodies to TGF-beta1 and -beta2 or exogenous TGF-beta3 peptide by local application and intraperitoneal injection at various times before and after surgery. At day 7 after surgery, addition of neutralizing antibodies to both TGF-beta1 and -beta2 significantly reduced the number and size of adhesions (P < 0.05) compared with the vehicle control. By contrast, exogenous addition of TGF-beta3 either had no effect or increased adhesion formation compared to the vehicle control. In conclusion, these results show that by blocking both TGF-beta1 and TGF-beta2 using neutralizing antibodies, it is possible to prevent abdominal adhesion formation.

Animals↗
PubMed2000

Real-time kinetic studies on the interaction of transforming growth factor alpha with the epidermal growth factor receptor extracellular domain reveal a conformational change model.

Transforming growth factor alpha (TGF-alpha), epidermal growth factor (EGF), and related factors mediate their biological effects by binding to the extracellular domain of the EGF receptor, which leads to activation of the receptor's cytoplasmic tyrosine kinase activity. Much remains to be determined, however, about the detailed molecular mechanism involved in this ligand-induced receptor activation. The determination of the binding mechanism and the related thermodynamic and kinetic parameters are of prime importance. To do so, we have used a surface plasmon resonance-based biosensor (the BIAcore) that allows the real-time recording of the interaction between TGF-alpha and the extracellular domain of the EGF receptor. By immobilizing different biotinylated derivatives of TGF-alpha on the sensor chip surface, we demonstrated that the N-terminus of TGF-alpha is not directly involved in receptor binding. By optimizing experimental conditions and interpreting the biosensor results by several data analysis methods, we were able to show that the data do not fit a simple binding model. Through global analysis of the data using a numerical integration method, we tested several binding mechanisms for the TGF-alpha/EGF receptor interaction and found that a conformational change model best fits the biosensor data. Our results, combined with other analyses, strongly support a receptor activation mechanism in which ligand binding results in a conformation-driven exposure of a dimerization site on the receptor.

Binding, Competitive↗
PubMed1998

Plasmid DNA encoding transforming growth factor-beta1 suppresses chronic disease in a streptococcal cell wall-induced arthritis model.

Transforming growth factor beta is a potent immunomodulator with both pro- and antiinflammatory activities. Based on its immunosuppressive actions, exogenous TGF-beta has been shown to inhibit autoimmune and chronic inflammatory diseases. To further explore the potential therapeutic role of TGF-beta, we administered a plasmid DNA encoding human TGF-beta1 intramuscularly to rats with streptococcal cell wall-induced arthritis. A single dose of 300 microg plasmid DNA encoding TGF-beta1, but not vector DNA, administered at the peak of the acute phase profoundly suppressed the subsequent evolution of chronic erosive disease typified by disabling joint swelling and deformity (articular index = 8.17+/-0. 17 vs. 1.25+/-0.76, n = 6, day 26, P < 0.01). Moreover, delivery of the TGF-beta1 DNA even as the chronic phase commenced virtually eliminated subsequent inflammation and arthritis. Both radiologic and histopathologic as well as molecular evidence supported the marked inhibitory effect of TGF-beta1 DNA on synovial pathology, with decreases in the inflammatory cell infiltration, pannus formation, cartilage and bone destruction, and the expression of proinflammatory cytokines that characterize this model. Increases in TGF-beta1 protein were detected in the circulation of TGF-beta1 DNA-treated animals, consistent with the observed therapeutic effects being TGF-beta1 dependent. These observations provide the first evidence that gene transfer of plasmid DNA encoding TGF-beta1 provides a mechanism to deliver this potent cytokine that effectively suppresses ongoing inflammatory pathology in arthritis.

Animals↗
PubMed1986

Is non-genic inheritance involved in carcinogenesis? A cytotactic model of transformation.

There is convincing evidence that the patterns formed by microtubules and by other fibres and organelles in ciliates are partly determined by non-genic inherited information, the so-called cytotactic information. There is also some evidence that this exists in metazoan cells and is perhaps involved in neoplastic transformation. On this background a cytotactic model of transformation which allows new interpretation of several characteristics of cancer cells has been developed. It proposes (a) that most cells contain cytotactic information, (b) that mechanisms to repair modifications of this information exist, and (c) that transformation may result when the cytotactic information is modified beyond repair. The model further proposes that (d) the modified cytotactic information is unevenly distributed between daughter cells at the following divisions so that cells with abnormal patterns, increasing pleomorphy and malignancy, and possibly altered gene functions are formed. The cytotactic transformation is proposed to take place in one or in two steps and to be inducible not only by many usual carcinogens but also by for example aborted cell divisions. A cytotactic interpretation of cancers induced by asbestos and of certain other observations is attempted.

Animals↗
PubMed1991

Cell cycle kinetics with supramitotic control, two cell types, and unequal division: a model of transformed embryonic cells.

We develop a mathematical model of cell cycle kinetics of transformed embryonic cells. The model includes supramitotic regulation, in which decisions regarding growth control are made at a point inside the cell division cycle and their impact extends to the next decision point, located in the next division cycle. Another feature is the presence of two varieties of cells, which switch from one to the other with given transition probabilities. The third factor considered is unequal division of cells, also defined in probabilistic terms. We provide a rigorous description of the model and derivation of its equations and analyze its asymptotic properties by defining and investigating an abstract semigroup of positive linear operators in appropriate state space. The spectral properties of the semigroup yield the balanced exponential growth law for the model. To compare the model to experimental data, we derive basic pedigree statistics, beta curves, and generation time correlations. We present numerical calculations based on measurements available for the embryonic cells. We conclude that to yield the experimentally obtained pedigree statistics, switches from one cell variety to the other must be quite infrequent.

Animals↗
PubMed1987

Macrophage cell lines transformed by the malignant histiocytosis sarcoma virus: increase of CSF receptors suggests a model for transformation.

The malignant histiocytosis sarcoma virus (MHSV) contains Ha-v-ras-related oncogenic sequences and rapidly transforms myeloid cells in vivo and in vitro. Myeloid cell lines can be derived which do not require growth factor for continued proliferation. We initiated this work to define the process of transformation leading to autonomy of cell growth in transformed myeloid cells. Five established cell lines were examined. All express macrophage-specific cell-surface antigens and exhibit several other properties typical for mature macrophages. Growth properties, growth factor release, and growth factor receptor presentation were examined: Release of growth factors is not a consistent feature. All cell lines show cell-density-independent colony formation and do not release self-stimulating factors, thus excluding autocrine stimulation as a model leading to transformation. All cell lines express unusually high levels of granulocyte-macrophage (GM)- and multi-CSF receptors and, except for one, M-CSF receptors. The high increase in GM-CSF and other growth factor receptors may be causally related to the transformed state of the cells. MHSV can be used as a tool to easily derive cell lines of the macrophage pathway as a model to study myeloid transformation, differentiation, and macrophage function.

Animals↗
PubMed1992

Two models for transforming auditory signals from head-centered to eye-centered coordinates.

Two models for transforming auditory signals from head-centered to eye-centered coordinates are presented. The vector subtraction model subtracts a rate-coded eye position signal from a topographically weighted auditory target position signal to produce a rate-code of target location with respect to the eye. The rate-code is converted into a place-code through a graded synaptic weighting scheme and inhibition. The dendrite model performs a mapping of head-centered auditory space onto the dendrites of eye-centered units. Individual dendrites serve as logical comparators of target location and eye position. Both models produce a topographic map of auditory space in eye-centered coordinates like that found in the primate superior colliculus. Either type can be converted into a model for transforming visual signals from retinal to head-centered coordinates.

Auditory Perception↗
PubMedDate not supplied

A Laplace transform pair model for spectral reconstruction.

A four-parameter Laplace transform pair model, which accurately reconstructs an experimental bremsstrahlung spectrum from attenuation data, is presented. Computed spectral values with both aluminum and copper attenuators generally agree with experimental 70-kVp data to better than 2%. Reconstructed spectra at other kVp's also show good agreement with published data.

Mathematics↗
PubMed2002

Modelling wastewater transformation in sewers based on ASM3.

A deterministic model for wastewater transformations in the sewer that includes activity in the wastewater and in the sewer wall biofilm was developed. It is based on the Activated Sludge Model No. 3 (ASM3). The mass transfer processes in the biofilm were modelled with the effectiveness approach. This approach allowed for fast calculation, required only a limited number of parameters and gave good results. The ASM3 related parameters were calibrated and validated with laboratory experiments. An equation for the aeration of the wastewater through the water surface was determined with a method based on the inert gas sulphur hexafluoride. The other model parameters such as wall roughness, attachment of particles to the biofilm and biofilm erosion were calibrated and validated with field experiments in a main sewer. The resulting model described the oxygen concentration and wastewater respiration well. It can be easily linked for integrated urban hydrology modelling with the WWTP Activated Sludge Model and the newly proposed River Water Quality Model No. 1.

Biofilms↗
PubMed1994

Effect of TGF-beta 1 on re-epithelialization of human keratinocytes in vitro: an organotypic model.

Transforming growth factor beta-1 (TGF-beta 1) has been shown to inhibit keratinocyte proliferation in vitro yet and migration was investigated in organotypic cultures after incisional wounding. Organotypic cultures provide a more in vivo-like epidermal tissue and may therefore respond in a different manner than previous culture models in which epidermal differentiation is incomplete. Without TGF-beta 1, keratinocytes were hyperproliferative in response to wounding. At doses of 2.5 ng/ml or greater, a delay in re-epithelialization was seen at 24 h post-wounding along with a reduction in hyperproliferation. By 48 h, however, re-epithelialization was complete in all cultures treated with TGF-beta 1. In particular, 7 ng/ml TGF-beta 1 inhibited proliferation yet had no effect on re-epithelialization by 48 h. These studies demonstrate that i) TGF-beta 1 induced a delay in re-epithelialization, ii) proliferation of wounded keratinocytes was not inhibited at 2.5 ng/ml doses of TGF-beta 1, and iii) at 7 ng/ml TGF-beta 1, re-epithelialization was complete by 48 h in spite of the profound inhibition of cell proliferation. In the organotypic model, TGF-beta 1 appears to alter re-epithelialization.

Cell Division↗
PubMedDate not supplied

Application of a Laplace transform pair model for high-energy x-ray spectral reconstruction.

A Laplace transform pair model, previously shown to accurately reconstruct x-ray spectra at diagnostic energies, has been applied to megavoltage energy beams. The inverse Laplace transforms of 2-, 6-, and 25-MV attenuation curves were evaluated to determine the energy spectra of these beams. The 2-MV data indicate that the model can reliably reconstruct spectra in the low megavoltage range. Experimental limitations in acquiring the 6-MV transmission data demonstrate the sensitivity of the model to systematic experimental error. The 25-MV data result in a physically realistic approximation of the present spectrum.

Humans↗
PubMed1988

Ventricular ejection fractions of linear transformation and ellipsoid models.

Eigenvolumes calculated from a linear transformation model were found previously to be linearly related to balloon volumes in excised hearts. The present study analyzed endocardial marker kinematics in intact, contracting left ventricles by biplane cinefluorography. Ejection fractions of the linear transformation model were compared by linear regression analysis with those of an ellipsoidal model, whose ejection fractions had been documented previously in closed and open-chest dog preparations. Data from 10 dogs indicated a correlation coefficient of 0.98 and a regression equation with close similarity to the line of identity. Ejection fractions calculated from the linear transformation model are concluded to be proportional to actual ejection fractions in intact, beating left ventricles.

Algorithms↗
PubMed1991

Product toxicity and cometabolic competitive inhibition modeling of chloroform and trichloroethylene transformation by methanotrophic resting cells.

The rate and capacity for chloroform (CF) and trichloroethylene (TCE) transformation by a mixed methanotrophic culture of resting cells (no exogenous energy source) and formate-fed cells were measured. As reported previously for TCE, formate addition resulted in an increased CF transformation rate (0.35 day-1 for resting cells and 1.5 day-1 for formate-fed cells) and transformation capacity (0.0065 mg of CF per mg of cells for resting cells and 0.015 mg of CF per mg of cells for formate-fed cells), suggesting that depletion of energy stores affects transformation behavior. The observed finite transformation capacity, even with an exogenous energy source, suggests that toxicity was also a factor. CF transformation capacity was significantly lower than that for TCE, suggesting a greater toxicity from CF transformation. The toxicity of CF, TCE, and their transformation products to whole cells was evaluated by comparing the formate oxidation activity of acetylene-treated cells to that of non-acetylene-treated cells with and without prior exposure to CF or TCE. Acetylene arrests the activity of methane monooxygenase in CF and TCE oxidation without halting cell activity toward formate. Significantly diminished formate oxidation by cells exposed to either CR or TCE without acetylene compared with that with acetylene suggests that the solvents themselves were not toxic under the experimental conditions but their transformation products were. The concurrent transformation of CF and TCE by resting cells was measured, and results were compared with predictions from a competitive-inhibition cometabolic transformation model. The reasonable fit between model predictions and experimental observations was supportive of model assumptions.

Binding, Competitive↗
PubMed1998

Analysis of metabolite formation pharmacokinetics after intravenous and oral administration of the parent drug using inverse Laplace transformation.

Models describing the plasma concentration-time curves of generated metabolite after iv and oral drug administration are presented. Utilizing numerical inverse Laplace transformation, the method can readily be used for parameter estimation and model simulation in conjunction with appropriate curve-fitting software. The approach is not limited to compartment modeling and can be applied to any linear pharmacokinetic system exhibiting hepatic and renal elimination of the parent drug. The model is formulated for single and multiple dosing of the precursor, including bolus doses and/or infusions for iv administration and sustained-release dosage forms for oral administration.

Administration, Oral↗
PubMed2001

Estimating log models: to transform or not to transform?

Health economists often use log models to deal with skewed outcomes, such as health utilization or health expenditures. The literature provides a number of alternative estimation approaches for log models, including ordinary least-squares on ln(y) and generalized linear models. This study examines how well the alternative estimators behave econometrically in terms of bias and precision when the data are skewed or have other common data problems (heteroscedasticity, heavy tails, etc.). No single alternative is best under all conditions examined. The paper provides a straightforward algorithm for choosing among the alternative estimators. Even if the estimators considered are consistent, there can be major losses in precision from selecting a less appropriate estimator.

Delivery of Health Care, Integrated↗
PubMed1985

Effect of coiling in a cochlear model.

Transformation of the three-dimensional equations of fluid motion into cylindrical coordinates allowed analysis of a coiled cochlear model by the WKB technique. The model includes a single transverse mode of basilar membrane deflection and inviscid fluid. The results calculated using realistic parameters for the guinea pig show no significant difference in the basilar membrane amplitude and phase between the straight and coiled models. Some differences exist in the fluid pressure found in the scala. The conclusion is that the macromechanical response is not significantly affected by coiling.

Acoustics↗
PubMed2003

Smad3 regulates senescence and malignant conversion in a mouse multistage skin carcinogenesis model.

Transforming growth factor beta (TGF-beta) is a growth-inhibitory cytokine for epithelial cells. In the mouse multistage skin carcinogenesis model, defects in TGF-beta 1 signaling reduce senescence in vitro and accelerate malignant progression in vivo. However, the precise postreceptor signaling pathways and specific roles played by Smad proteins in this process have not been defined. Here we show that senescence of v-ras(Ha)-transduced Smad3 null keratinocytes is delayed, whereas overexpression of Smad3, but not Smad2 or Smad4, induced senescence. The TGF-beta 1 target genes c-myc and p15(ink4b) were deregulated in the absence of Smad3. When transplanted to a graft site on nude mice, the v-ras(Ha)-transduced Smad3 null keratinocytes underwent rapid conversion from benign papilloma to malignant carcinoma, whereas wild-type keratinocytes predominantly formed papillomas. These results link Smad3-mediated regulation of growth control genes to senescence in vitro and tumor suppression in vivo.

Animals↗
PubMed2001

Blink artifact elimination in electroencephalographic records based on discrete cosine transform domain modeling.

A method for eliminating blink artifacts that contaminate electroencephalographic (EEG) records is introduced. The proposed method enables a direct estimation of blink artifacts without the use of the simultaneously recorded electroculargraphic (EOG) signal. The estimation of blink artifacts in the EEG was achieved by modeling in the discrete cosine transform (DCT) domain. The DCT coefficients of the blink artifact were sufficiently represented by a system transfer function with a low model order of 4. Two cases were investigated: one was blink artifact elimination for the background EEG and the other was for the somatosensory evoked potentials. The effectiveness of the proposed method was demonstrated in an experimental study based on actual EEG data of 11 healthy subjects. The simplicity and effectiveness of the proposed method suggest that blink artifact elimination using DCT domain modeling can possibly be applied in various areas of neuroscience for improving EEG quality.

Adolescent↗