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PubMed1981

The use of optical Fourier transforms to diagnose pleomorphism, size and chromatin clumping in nuclear models.

Nuclear features of size, pleomorphism and chromatin clumping are distinctive and quantifiable in the optical Fourier transform of the nucleus. This is shown in photographs of models, tracings and hematoxylin-stained impression smears of various types of nuclei. The size of the transform is inversely proportional to the size of the nucleus. Irregularities in shape (pleomorphism) produce radially symmetric rays of light in the transform. The effect of chromatin clumping is to give a mottled pattern superimposed on the pleomorphism pattern. The transform features can be measured in real time using a ring-wedge or similar detector. These procedures might be used for both automatic screening and objective quantification of diagnoses.

Cell Nucleus↗
PubMed1997

Malignant transformation of immortalized human bronchial epithelial cells by asbestos fibers.

Although asbestos is a well-established lung carcinogen, there currently is no suitable human cell model in which to examine the underlying cellular and molecular changes associated with fiber-mediated bronchial carcinogenesis. Using a recently established transformation model based on a human papillomavirus-immortalized human bronchial epithelial cell line, we successfully transformed these BEP2D cells after a single, 7-day treatment with a 20-microgram/ml (4 micrograms per cm2 area) dose of Union Internationale Contre le Cancer (UICC) Rhodesian chrysotile fibers. Asbestos treatment resulted in a surviving fraction of 0.18 compared to control cells. Transformed cells developed through a series of sequential steps, including altered growth kinetics, resistance to serum-induced terminal differentiation, and anchorage-independent growth, before becoming tumorigenic to form progressively growing tumors in nude mice. Seven tumorigenic cell lines were isolated and determined to be of human epithelial origin based on immunofluorescent staining of keratin and isozyme analysis. Analysis of tumor DNA revealed no mutations at either codon 12 or 13 in any the ras oncogenes. An independent role for K-ras mutation in fiber carcinogenesis, therefore, cannot be confirmed. This model provides a unique opportunity to study the cellular and molecular changes at the various stages in fiber-mediated neoplastic transformation of human bronchial epithelial cells.

Animals↗
PubMed1994

[Experimental test of a model of memory-representation-generation in learning and recognition].

A highly structured set of stimuli was used in this study. Each stimulus had four binary attributes, whose values were determined so that any two stimuli could be transformed into each other by changing values of one or more attributes. In one experiment, 93 undergraduates rated similarity of paired stimuli. In another experiment, the same subjects learned three stimuli which were presented one after another for 10 seconds each. Later, in the recognition task, they made "old" or "new" judgment and rated the confidence of their judgment for each of the test stimuli. Two groups of subjects served the two experiments in different order. The results showed that (1) the rated similarity between the paired stimuli is a monotonically decreasing function of the number of transformations needed to get the pair equal, (2) the recognition confidence for new stimuli is significantly higher for stimuli generated by relevant transformations from the learned stimuli than for stimuli not so generated. The results support a model of memory-representation-generation (Suto, 1987, 1988), but not "prototype plus transformation model" nor "context model".

Adult↗
PubMed2000

A mouse model for valproate teratogenicity: parental effects, homeotic transformations, and altered HOX expression.

Valproate (VPA) is one of several effective anti-epileptic and mood-stabilizing drugs, many of which are also potent teratogens in humans and several other mammalian species. Variable teratogenicity among inbred strains of laboratory mice suggests that genetic factors influence susceptibility. While studying the genetic basis for VPA teratogenicity in mice, we discovered that parental factors influence fetal susceptibility to induced malformations. Detailed examination of these malformations revealed that many were homeotic transformations. To test whether VPA, like retinoic acid (RA), alters HOX expression, pluripotent human embryonal carcinoma cells were treated with VPA or RA and Hox expression assessed. Altered expression of specific Hox genes may thus account for the homeotic transformations and other malformations found in VPA-treated fetuses.

Abnormalities, Drug-Induced↗
PubMed2006

Invariant visual object recognition: a model, with lighting invariance.

How are invariant representations of objects formed in the visual cortex? We describe a neurophysiological and computational approach which focusses on a feature hierarchy model in which invariant representations can be built by self-organizing learning based on the statistics of the visual input. The model can use temporal continuity in an associative synaptic learning rule with a short term memory trace, and/or it can use spatial continuity in Continuous Transformation learning. The model of visual processing in the ventral cortical stream can build representations of objects that are invariant with respect to translation, view, size, and in this paper we show also lighting. The model has been extended to provide an account of invariant representations in the dorsal visual system of the global motion produced by objects such as looming, rotation, and object-based movement. The model has been extended to incorporate top-down feedback connections to model the control of attention by biased competition in for example spatial and object search tasks. The model has also been extended to account for how the visual system can select single objects in complex visual scenes, and how multiple objects can be represented in a scene.

Animals↗
PubMed1986

A two-stage nonlinear cochlear model possesses automatic gain control.

A model of the cochlea is explored using as stimuli two simultaneously presented sinusoids of equal amplitude. The model consists of two stages: a linear bandpass filter, followed by a reservoir-type representation of the hair-cell/nerve-fiber complex. Fast Fourier transforms of the model's output were computed. While the amplitudes of the individual response components were strongly nonlinear functions of intensity, the ratio of the magnitudes of the response components at the frequencies of the two stimulating sinusoids was found to be nearly equal, over a wide intensity range, to the ratio of the amplitudes which those stimulating sinusoids possessed at the output of the filter. Thus the reservoir stage exerts "automatic gain control".

Adaptation, Physiological↗
PubMed1992

Rapid, complete and reversible transformation by v-sis precedes irreversible transformation.

v-sis is the oncogene of simian sarcoma virus, but whether tumor growth is maintained by v-sis expression alone or requires additional changes is unknown. To distinguish these possibilities we studied a model of reversible transformation including tumorigenicity using NIH3T3 cells bearing a metallothionein promoter-v-sis construction. Cells subcultured from 10 out of 18 tumors from athymic mice, all less than 0.1 g and less than or equal to 21 days in age, reverted to a normal phenotype but exhibited transformation upon addition of zinc as judged by morphology, growth rate, saturation density and anchorage independence of growth. Thus, activation of v-sis alone is sufficient for initiation and early autocrine-based growth of tumors. However, the cells from the remaining and predominantly larger, 0.5 +/- 0.7 g, tumors did not revert and exhibited zinc-independent transformation as judged by the same criteria. Southern analysis and examination of the regulation of v-sis product expression in cells derived from these tumors showed no change in zinc-dependent and reversible regulation of v-sis sequences. These results suggest that subsequent tumor growth strongly favors acquisition of additional irreversible change(s) in the tumor cell genome at high frequency (44%). Thus an early event of a multistep process stimulated by v-sis-dependent transformation best accounts for the sum of results.

3T3 Cells↗
PubMed2006

Application of the fast-Fourier-transform-based volume integral equation method to model volume diffraction in shift-multiplexed holographic data storage.

Numerical simulation of diffraction on thick holographic gratings in shift-multiplexed optical data storage application is presented. The grating is generated by the interference of a spherical reference wave and a plane signal wave corresponding to a single pixel of the input data page. To describe diffraction on this weak-index-modulated grating, we use the volume integral equation in the first Born approximation. This description yields a convolution integral that can be efficiently evaluated by a 3D fast Fourier transform (FFT) technique. For a 51.2 microm recording layer thickness, a serial-divided single personal computer code was built based on parallel FFT coding principles. Diffracted electric field and Poynting-vector distributions are calculated for probe beams spatially shifted with respect to the reference beams. The shift selectivity curves show significant differences from previous analytical calculations based on paraxial propagation and infinite gratings, as they have monotonic decrease in all three directions instead of sinclike functions with Bragg nulls. With the chosen numerical aperture of 0.6 and linear polarization, both the scalar and vector calculations provided similar results within 5%.

Journal Article↗
PubMed2004

Transforming growth factor-betas in a rat model of neonatal posthaemorrhagic hydrocephalus.

Posthaemorrhagic ventricular dilatation (PHVD) is a common complication of intraventricular haemorrhage in premature infants. The aim of this study was to investigate the role of transforming growth factor-betas (TGF-betas), a family of polypeptides with potent desmoplastic properties, in the aetiology of PHVD in a newly developed neonatal rat model of this disorder. Pups were injected with citrated rat blood or artificial cerebrospinal fluid (ACSF) into alternate lateral ventricles on postnatal days 7 and 8. The brains were perfusion-fixed 14 days later and immunohistochemistry was performed for TGF-beta1, -beta2 and -beta3, p44/42 mitogen-activated protein (MAP) kinases, and the extracellular matrix proteins laminin, vitronectin and fibronectin. Ventricular dilatation occurred in 58.3% of animals injected with blood and 36.7% of those injected with ACSF. Periventricular immunoreactivity for TGF-beta1 and -beta2 increased in injected animals irrespective of the presence or absence of ventricular dilatation, although the levels of both isoforms tended to be higher in animals with hydrocephalus. TGF-beta3 immunoreactivity was elevated in hydrocephalic rats only. The immunolabelling for phosphorylated p44/42 MAP kinases rose in a pattern similar to that for TGF-beta1 and -beta2. Expression of TGF-betas was accompanied by deposition of the extracellular matrix proteins fibronectin, laminin and vitronectin. The changes caused by injection of ACSF were the same as those caused by injection of blood. Our results raise the possibility that expression of TGF-betas, together with extracellular matrix protein deposition, may be involved in the development and/or maintenance of hydrocephalus after ventricular distension due to haemorrhage in the neonate.

Animals↗
PubMed1987

Formation of octacalcium phosphate and subsequent transformation to hydroxyapatite at low supersaturation: a model for cartilage calcification.

By means of X-ray powder diffraction (XRD), octacalcium phosphate (OCP, Ca8H2(PO4)6 X 5H2O, Ca/P = 1.33) has been shown to be a metastable precursor of hydroxyapatite (HA, Ca10(PO4)6(OH)2, Ca/P = 1.67) during de novo HA formation in aqueous solutions containing [CaCl2] = 1.0-2.0 mM and [Na2HPO4] less than or equal to 3 mM, kept at 37 degrees C, 300 mosM and stirred gently at 150 rpm. At the precipitation boundary with initial pH = 7.4, OCP is stable for at least 24 hours when [Ca] = 1.0 mM, and is less stable when [Ca] = 2.0 mM, transforming into a mixture of OCP and HA within 24 hours. Almost complete transformation to HA within 24 hours takes place with high [Ca] and high [Pi]. Statistical analysis of the pH 7.4 precipitation boundary data supports the XRD findings: although [Ca][Pi] values vary significantly (P less than 0.001) with [Ca] (2.70 +/- 0.05 mM2 for [Ca] = 1.0 mM and 2.00 +/- 0.10 mM2 for [Ca] = 2.0 mM), [Ca]1.33[Pi] values do not vary with [Ca] suggesting that the initial precipitation process is 6(1.33 Ca + Pi)----OCP. With initial pH = 7.6, a different precipitation boundary with lower [Ca][Pi] values has been determined. These findings strongly support the fact that rat epiphyseal cartilage fluid which has [CaUF][PiUF] = 2.6 mM2 (UF = ultrafiltrate) and pH 7.6 [2] should be able to support de novo calcification.

Calcification, Physiologic↗
PubMed1987

Biologically motivated cancer risk models.

A two-stage dose response model is proposed for use in cancer risk assessment. The model assumes that transformation probabilities and cellular dynamics are exposure- and time-dependent.

Animals↗
PubMed1997

Neoplastic transformation of cultured mammalian cells by estrogens and estrogenlike chemicals.

Estrogens are clearly carcinogenic in humans and rodents but the mechanisms by which these hormones induce cancer are only partially understood. Stimulation of cell proliferation and gene expression by binding to the estrogen receptor is one important mechanism in hormonal carcinogenesis; however, estrogenicity is not sufficient to explain the carcinogenic activity of all estrogens because some estrogens are not carcinogenic. Estrogens are nonmutagenic in many assays but exhibit specific types of genotoxic activity under certain conditions. We have studied extensively the mechanisms by which estrogens induce neoplastic transformation in a model in vitro system and our findings are summarized in this review. 17beta-Estradiol (E2) and diethylstilbestrol (DES) and their metabolites induce morphological and neoplastic transformation of Syrian hamster embryo (SHE) cells that express no measurable levels of estrogen receptor. Treatment of the cells with E2 or DES fails to induce DNA damage, chromosome aberrations and gene mutations in SHE cells but results in numerical chromosome aberrations (aneuploidy) that could arise from microtubule disruption or disfunction of mitotic apparatus. Estrogen-induced genotoxicity is detected in cells following treatment with estrogen metabolites or following exogenous metabolic activation of estrogens. The estrogens induce DNA adduct formation that is detected by 32P-postlabeling. Both aneuploidy induction and DNA damage caused by DNA adduct formation correlate with the estrogen-induced cell transformation and may be important in hormonal carcinogenesis. We propose that multiple effects of estrogens acting together cause genetic alterations leading to cell transformation.

Aneuploidy↗
PubMed1997

Thermal and diffusion processes in laser-induced stress relaxation and reshaping of cartilage.

The thermodynamic characteristics of the 'bound-to-free' phase transformation of water are studied by means of differential microcalorimetry and FTIR spectroscopy. This phase transition controls the stress relaxation and reshaping of cartilage which we have observed previously under moderate laser heating. It is shown that the FTIR spectrum of bound water in cartilage differs from that of free water in cartilage, and that both show differences to the FTIR spectrum of pure water. The proportion of bound water in cartilage is found to be of the order 4%. We have examined water liberation and absorption kinetics and found them to be controlled by diffusion through the tissue and also by the bound-to-free water transformation. The theoretical modelling and experimental data allowed calculation of diffusion coefficients and the activation energy for water transfer. The latter was found to be close to the heat of phase transformation of water. We have established that the drying and wetting processes in cartilage are reversible (fully or in a part, depending on the temperature of preliminary drying) and can be described by identical solutions of the diffusion problem, with coefficients of water diffusion being the same. The mechanism of water diffusion in cartilaginous tissue is also discussed.

Animals↗
PubMed1994

Muscarinic receptors transform NIH 3T3 cells through a Ras-dependent signalling pathway inhibited by the Ras-GTPase-activating protein SH3 domain.

Expression of certain subtypes of human muscarinic receptors in NIH 3T3 cells provides an agonist-dependent model of cellular transformation by formation of foci in response to carbachol. Although focus formation correlates with the ability of the muscarinic receptors to activate phospholipase C, the actual mitogenic signal transduction pathway is unknown. Through cotransfection experiments and measurement of the activation state of native and epitope-tagged Ras proteins, the contributions of Ras and Ras GTPase-activating protein (Ras-GAP) to muscarinic receptor-dependent transformation were defined. Transforming muscarinic receptors were able to activate Ras, and such activation was required for transformation because focus formation was inhibited by coexpression of either Ras with a dominant-negative mutation or constructs of Ras-GAP that include the catalytic domain. Coexpression of the N-terminal region of GAP or of its isolated SH3 (Src homology 3) domain, but not its SH2 domain, was also sufficient to suppress muscarinic receptor-dependent focus formation. Point mutations at conserved residues in the Ras-GAP SH3 domain reversed its action, leading to an increase in carbachol-dependent transformation. The inhibitory effect of expression of the Ras-GAP SH3 domain occurs proximal to Ras activation and is selective for the mitogenic pathway activated by carbachol, as cellular transformation by either v-Ras or trkA/nerve growth factor is unaffected.

3T3 Cells↗
PubMed1989

A survey of models for repeated ordered categorical response data.

We survey models for analysing repeated observations on an ordered categorical response variable. The models presented are univariate models that permit correlation among repeated measurements. The models describe simultaneously the dependence of marginal response distributions on values of explanatory variables and on the occasion of response. We present models for three transformations of the response distribution: cumulative logits, adjacent-category logits, and the mean for scores assigned to response categories. We discuss three methods for fitting the models: maximum likelihood, weighted least squares, and semi-parametric. Weighted least squares is easily implemented with SAS, as illustrated with a study designed to compare a drug with a placebo for the treatment of insomnia.

Classification↗
PubMed2001

Professional development for university faculty through service.

The purpose of this article is to identify the contexts for service that are useful for the professional development of university faculty as well as to suggest a model for delivering the work that is part of this type of professional development. The article accomplishes this goal by examining contexts for service, related activities and transformable skills. The model suggested for developing and implementing service activities consists of three components: 1) an initiating force, 2) ways for testing and sharing ideas, and 3) proposed solutions.

Journal Article↗
PubMed2002

The vertebrate skeletal muscle thick filaments are not three-stranded. Reinterpretation of some experimental data.

Computer simulation of mass distribution within the model and Fourier transforms of images depicting mass distribution are explored for verification of two alternative modes of the myosin molecule arrangement within the vertebrate skeletal muscle thick filaments. The model well depicting the complete bipolar structure of the thick filament and revealing a true threefold-rotational symmetry is a tube covered by two helices with a pitch of 2 x 43 nm due to arrangement of the myosin tails along a helical path and grouping of all myosin heads in the crowns rotated by 240 degrees and each containing three cross-bridges separated by 0 degrees, 120 degrees, and 180 degrees. The cross-bridge crown parameters are verified by EM images as well as by optical and low-angle X-ray diffraction patterns found in the literature. The myosin tail arrangement, at which the C-terminus of about 43-nm length is near-parallel to the filament axis and the rest of the tail is quite strongly twisted around, is verified by the high-angle X-ray diffraction patterns. A consequence of the new packing is a new way of movement of the myosin cross-bridges, namely, not by bending in the hinge domains, but by unwrapping from the thick filament surface towards the thin filaments along a helical path.

Actin Cytoskeleton↗