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PubMed1997

LDL receptor family-dependent and -independent pathways for the internalization and digestion of lipoprotein lipase-associated beta-VLDL by rat vascular smooth muscle cells.

Lipoprotein lipase (LPL) promotes the binding and internalization of beta-VLDL (very low density lipoprotein) by many cell types. We examined the function of receptors in the LDL receptor family (LRF) and heparan sulfate proteoglycans (HSPG) in the metabolism of LPL-associated beta-VLDLa by rat vascular smooth muscle cells (VSMCs) in culture. These cells express LDL receptor-related protein and the VLDL receptor, but not the LDL receptor. LPL greatly increased the binding of 125I-labeled beta-VLDL to VSMCs at 4 degrees C. Binding was almost entirely inhibited by heparin, but essentially unaffected by the potent LRF-antagonist, receptor-associated protein (RAP), indicating that LRFs do not contribute significantly to the VSMC binding capacity for LPL-associated beta-VLDL. At 37 degrees C, RAP inhibited the rapid internalization of LPL-associated 125I-labeled beta-VLDL and the digestion of the beta-VLDL into trichloroacetic acid soluble radioactivity; these processes still occurred, but at a decreased rate. RAP did not inhibit the ability of beta-VLDL-LPL complex to stimulate VSMC ACAT activity. Furthermore, in Oil red-O histochemistry experiments, which model foam cell transformation in vitro, RAP paradoxically increased cholesteryl ester storage in VSMCs treated with beta-VLDL and LPL under specific cell culture conditions. These results support a model in which the internalization of LPL-associated beta-VLDL by VSMCs is mediated by two pathways, one involving LRFs and a second that is independent of LRFs, probably involving direct uptake by HSPG. The LRF-dependent pathway leads to less cellular storage of cholesteryl ester and thus may be antiatherogenic under certain conditions.

Animals↗
PubMed1999

Coordinated modulation of the fibroblast growth factor dual receptor mechanism during transformation from human colon adenoma to carcinoma.

Basic fibroblast growth factor (bFGF) is dependent on heparan sulphate for its ability to activate the cell surface signal transducing receptor. We have investigated the FGF dual receptor mechanism in a novel model of the transformation from human colon adenoma to carcinoma in vitro. Reverse transcription-polymerase chain reaction showed that mRNA for FGF receptors 1 and 2 were expressed in both the adenoma and carcinoma cells whereas immunocytochemistry showed that the expression of the FGF R1 was reduced significantly in the carcinoma cells. We have reported previously that the composition and sequence of human colon adenoma and carcinoma heparan sulphate (HS) differ in a defined and specific manner. The functional significance of these changes was assessed by affinity co-electrophoresis, which showed that the affinity of adenoma HS for bFGF was 10-fold greater than that of the carcinoma HS (Kd 220 nM vs. 2493 nM, respectively). In addition, Northern studies of the expression of syndecan 1 and 4 mRNA showed that proteoglycan core protein expression was reduced significantly in the carcinoma cells. These findings were associated with a reduced biological response to bFGF in the carcinoma cells that could be partially reversed by the addition of exogenous heparin, suggesting that both the proteoglycan and signal transducing receptor control the cells' response to bFGF.

Adenoma↗
PubMed2005

Kinetic modeling of aldehyde adsorption rates on bare and aminopropylsilyl-modified silica gels by ultra-rapid-scanning fourier transform infrared spectrometry.

Enhancements of a model capable of precisely defining rates of adsorption in terms of a Langmuir isotherm and determined from infrared and pressure data collected in the millisecond time regime are described in detail. Rates of adsorption are determined for formaldehyde and acetaldehyde exposed to bare and aminopropylsilyl-derivatized silica gel. The model fits the collected data by varying the number of adsorption sites and the adsorption and desorption rate constants and determines the best fit based on the measured IR absorbance, partial pressure, exposure backpressure, number of adsorption sites, and time. The rate of adsorption onto irregular-shaped silica gel was faster than the rate onto the corresponding spherical silica gel. Formaldehyde was adsorbed more efficiently than acetaldehyde on APS silica gel than on bare silica gel, whereas acetaldehyde was adsorbed more efficiently than formaldehyde on underivatized silica, indicating the possibility that formaldehyde is adsorbed through the formation of a Schiff base.

Journal Article↗
PubMed1998

Establishment of a functional HGF/C-MET autocrine loop in spontaneous transformants of WB-F344 rat liver stem-like cells.

A model of spontaneous malignant transformation was used to evaluate the molecular changes that take place in WB-F344 rat liver epithelial cells during neoplastic transformation and tumorigenesis. A comparison of wild-type low-passage WB-F344 cells to spontaneously transformed tumor cell lines revealed that the majority of the tumor cell lines have an increased capacity for autonomous proliferation and motility when maintained in serum-free media. In the current study, we show that c-met is expressed at some level in wild-type WB-F344 cells and in all of the spontaneously transformed tumor cell lines, and that 9/16 of the tumor cell lines have acquired hepatocyte growth factor (HGF) expression. In vitro growth of HGF-expressing tumor cell lines is inhibited as much as 68% by the addition of neutralizing antibodies to HGF or antisense HGF oligonucleotides, indicating that the production of HGF by the tumor cells is partially responsible for driving autonomous proliferation in a subset of tumor cell lines. Furthermore, conditioned media collected from HGF-expressing tumor cell lines stimulates DNA synthesis in wild-type WB-F344 cells, and this effect can be abrogated by pre-incubation of the conditioned media with neutralizing antibodies to HGF. Because HGF is a motility-promoting growth factor, all cell lines were evaluated to determine if expression of HGF stimulated motogenesis. All tumor cell lines (regardless of HGF expression) were highly motile in comparison with wild-type WB-F344 cells, with a 3.5-fold to 20-fold greater number of motile cells. The high basal rate of motility characteristic of the tumor cell lines is not a result of the production of HGF, because it is also a property of the cell lines that do not express HGF messenger RNA. Furthermore, tumor cell motility is not inhibited by antisense oligonucleotides or neutralizing antibodies. Establishment of an autocrine HGF/c-met loop in a subset of spontaneously transformed WB-F344 cell lines may influence development and/or expression of the tumorigenic phenotype by driving cellular proliferation.

Animals↗
PubMed2003

Using multiple structure alignments, fast model building, and energetic analysis in fold recognition and homology modeling.

We participated in the fold recognition and homology sections of CASP5 using primarily in-house software. The central feature of our structure prediction strategy involved the ability to generate good sequence-to-structure alignments and to quickly transform them into models that could be evaluated both with energy-based methods and manually. The in-house tools we used include: a) HMAP (Hybrid Multidimensional Alignment Profile)-a profile-to-profile alignment method that is derived from sequence-enhanced multiple structure alignments in core regions, and sequence motifs in non-structurally conserved regions. b) NEST-a fast model building program that applies an "artificial evolution" algorithm to construct a model from a given template and alignment. c) GRASP2-a new structure and alignment visualization program incorporating multiple structure superposition and domain database scanning modules. These methods were combined with model evaluation based on all atom and simplified physical-chemical energy functions. All of these methods were under development during CASP5 and consequently a great deal of manual analysis was carried out at each stage of the prediction process. This interactive model building procedure has several advantages and suggests important ways in which our and other methods can be improved, examples of which are provided.

Algorithms↗
PubMed1991

Quantitative characterization of hormone receptors by a nonlinear regression approach.

This paper describes a mathematical model for the quantification of receptors based only upon the total bound values as a function of the total ligand concentration. In contrast to methods relying on linearization transformations, this nonlinear model requires more sophisticated computation, however, avoids loss of material for determination of nonspecific binding in competed tubes. Monte-Carlo simulation indicated high stability of this model against random experimental error. The androgen receptor of the male gerbil (Meriones unguiculatus) ventral prostate is characterized using the described nonlinear computation.

Androgens↗
PubMed1999

Metastatic conversion of chemically transformed human cells.

A linear model for human cell metastasis has been developed in vitro from chemically transformed normal human cells. The chemically transformed cells are nontumorigenic in nude mice, but can be converted to a tumorigenic phenotype by transfection with a nondirectional cDNA library or antisense cDNA to the ML-1 gene. The primary transfected cell line (TR1T) forms localized, progressively growing tumors in nude mice that do not invade into the surrounding tissue. This tumorigenic TR1T cell line could be advanced into a metastatic stage following an additional transfection (TR2M cell line) with the cDNA expression library or antisense cDNA to the ML-1 gene. Metastatic cells, selected from tumors that were attached to internal organs, exhibited an increase in invasiveness as measured in vitro using an invasion chamber. The metastatic cells also exhibited an increased expression of matrix metalloproteinase-1 (MMP-1), although MMP-1 was not part of the cDNA that was transfected into either the TR1T cells or the doubly transfected metastatic TR2M cells. These data suggest that the increase in MMP-1 expression was a secondary downstream event responding to an upstream genetic change that initiated the conversion of cells from a tumorigenic to a metastatic stage. In summary, human cell lines representing premalignant, malignant, and metastatic phenotypes have been established in culture that can be used to identify gene changes that occur as normal human cells progress to a metastatic stage during tumor development. One gene, ML-1, that is found in the expression library appears to be involved in malignant progression, because ML-1 antisense cDNA will convert chemically transformed cells to both tumorigenic and metastatic stages, and cells from both local and metastatic tumors have a reduced or complete loss of expression of the ML-1 gene.

Animals↗
PubMed1995

Forced midexpiratory time: reference values and the effect of cigarette smoking.

BACKGROUND: Forced midexpiratory time (FET25-75%), the time required to exhale from 25 to 75% of forced vital capacity (FVC), has been advocated as a relatively volume-independent measure of obstruction. Previous estimates of normal FET25-75% have not systematically studied the effect of age, height, sex, and smoking history. METHODS: We analyzed flow-volume loops from 369 normal lifetime nonsmokers and smokers, a random sample of the population of Michigan. Linear models including age and/or height were considered, with and without logarithmic transformation. RESULTS: The best models used age, or age and height, and no transformation. Age and height contributed much less to the variability of FET25-75% than to spirometric flows previously investigated. The largest r2 was found in the male smokers, with the largest contribution from age, suggesting a smoking effect. CONCLUSIONS: As age was the major contributor to the value of FET25-75% and that contribution was small, we suggest the use of simplified age-stratified reference values derived from our data.

Adult↗
PubMed1990

Dietary restriction delays gastric emptying in rats.

In rats allowed to eat for only 2 h per day, gastric emptying of three different meals [poached egg white, glucose (0.5 kcal/ml) and physiological saline, each labelled with 60 MBq of technetium-99m tin colloid visualized using a gamma camera] was markedly slowed 8 h after the last meal. Mean body weight in rats on the restricted feeding schedule was 80% of the weight of free-feeding controls. Gastric emptying curves for all three meals in controls were best described using loge transformed counts. Other models used were linear and square root. For each of the three meals, the percentage remaining in the stomach at 120 min was estimated using linear regression of gastric contents, transformed if necessary to yield the best curve against time. At 120 min, % gastric contents (mean +/- SEM) were 19.5 +/- 5.6 (egg), 15.5 +/- 6.27 (glucose) and 27.1 +/- 7.48 (saline) in control rats. After 4 months restriction, the corresponding figures were 75.2 +/- 4.04, 81.5 +/- 4.75 and 70.3 +/- 5.83. After 3 months of free feeding, emptying rates of the three meals were not significantly different from control values. We conclude that dietary restriction causes profound changes in gastric emptying by unknown mechanisms which may be operating in patients with anorexia nervosa.

Animals↗
PubMed2007

Simulating the transformation of heavy metals during coal or sewage sludge combustion.

A mathematical model (FPM) is presented to predict the transformation of heavy metals in the downstream of combustor or incinerator. The model accounts for the transformation of heavy metals through the combined effect of condensation, nucleation, coagulation, external force and thermophoresis force. The calculation of heavy metals is embodied in the post-processor appended to Fluent soft. Before the simulation, velocity, temperature, PbCl2 concentration and other initial parameters are obtained by experiment. In addition, the transformation of PbCl2 is also experimentally studied. The comparison of experimental and predicted results indicate that the fine particle model (FPM) is valid for predicting the transformation of heavy metals in the downstream of incinerator or combustor.

Coal↗
PubMed1993

Oncogene transformation can induce tolerogenicity in murine macrophages after down-regulation of immunogenicity without altering major histocompatibility complex antigen expression.

In vitro studies on cell lines may allow analyses of the mechanisms of immunogenicity and tolerogenicity in cells. We used a model of oncogenic transformation of an established murine macrophage cell line and report here that one v-mos-transformed clone expressing unaltered high amounts of MHC class I and II antigens does not induce proliferation of unprimed T cells in primary mixed lymphocyte reactions, in sharp contrast to its non-transformed parental cells. Interestingly, this clone induces specific unresponsiveness, as revealed by the lack of responsiveness of MHC-specific T cells when subsequently exposed to the pertinent MHC alloantigens in immunogenic form but unaltered MHC-third party responsiveness of the naive spleen T cells. Furthermore, the accessory function of this clone is strongly reduced. These functional defects could be overcome by the addition of exogenous interleukin-1 alpha (IL-1 alpha). Analysis of mRNA expression showed a significant and selective reduction of IL-1 alpha mRNA levels when compared with parental cells.

Animals↗
PubMed2004

Exogenous Smad3 accelerates wound healing in a rabbit dermal ulcer model.

Exogenous administration of transforming growth factor-beta (TGF-beta) improves wound healing by affecting cellular and molecular events involved in tissue repair. But mice with a deficiency of a key TGF-beta signaling intermediate, Smad3, paradoxically showed accelerated cutanenous wound healing, suggesting that endogenous Smad3 had inhibitory effect on cutaneous wound healing. Here we investigated the effect of exogenous expression of Smad3 in dermal fibroblasts on cutaneous wound healing. Subcutaneous injection of adenovirus-containing Smad3 complementary DNA (AdCMV-Smad3) targeting mainly dermal fibroblasts accelerated tissue repair following full-thickness dermal round wounds in rabbit ear as judged by the size of granulation tissue area, number of capillaries, and re-epithelialization rate of the wounds. Expressions of alpha-smooth muscle actin (alpha-SMA), vascular endothelial growth factor (VEGF), and fibroblast growth factor receptor were upregulated in the wounded area injected with AdCMV-Smad3. Consistent with the in vivo findings, overexpression of Smad3 induced alpha-SMA, VEGF, and TGF-beta1 expression and augmented chemotactic response in cultured dermal fibroblasts. Therefore, exogenous administration of Smad3 targeting dermal fibroblasts accelerated tissue repair in a rabbit dermal ulcer model by affecting fibroblast responses associated with wound healing. The results suggest that Smad3, when overexpressed in dermal fibroblasts, can promote wound healing.

Actins↗
PubMed1995

Conditional transformation of mouse liver epithelial cells. An in vitro model for analysis of genetic events in hepatocarcinogenesis.

Primary rodent and human hepatocytes have a very limited lifespan in culture and are not readily applicable to transformation studies in vitro. To facilitate the investigation of early genetic events involved in hepatocarcinogenesis, we examined a transformation assay system utilizing conditionally immortalized mouse liver epithelial cells as an alternative to primary hepatocytes. By infecting primary mouse hepatocytes with a recombinant retrovirus carrying a temperature-sensitive simian virus 40 large T antigen gene, two mouse liver epithelial cell lines, CHST8 and CHST10-2.1, were established. Because of the heat-labile nature of the large T antigen, the cell lines proliferated rapidly at 33 degrees C, but were growth-arrested at 39 degrees C. Because activated c-H-ras and c-myc oncogenes are frequently found to be involved in mouse hepatocarcinogenesis in vivo, we assessed whether those oncogenes can complement the immortalizing function of the large T antigen at the nonpermissive temperature. When CHST8 cells were doubly transfected with activated c-H-ras and c-myc at 33 degrees C, they exhibited clonal growth ability even after shifting the temperature to 39 degrees C. However, neither c-H-ras nor c-myc alone allowed growth at 39 degrees C. On the other hand, c-H-ras alone was sufficient for overcoming the growth defect of CHST10-2.1 cells at 39 degrees C, whereas c-myc alone was again ineffective. Northern blot studies revealed that endogenous c-myc expression was significantly downregulated in the parental CHST8 cells after a temperature shift from 33 to 39 degrees C. In contrast, in the parental CHST10-2.1 cells, appreciable c-myc expression was observed at both temperatures. These results indicate that c-H-ras and c-myc can cooperate in complementing the ability of the temperature-sensitive large T antigen to immortalize mouse liver cells at the nonpermissive temperature. In addition, the mutant c-H-ras, but not c-myc, cooperated with the functional T antigen at 33 degrees C to allow growth in soft agarose of the CHST8 and CHST10-2.1 cell lines. However, cell lines carrying mutant c-H-ras and overexpressing c-myc were unable to grow in soft agarose at 39 degrees C. Thus, the two cellular oncogenes were insufficient for full transformation of the liver epithelial cells. The present in vitro model should be useful for investigating molecular events involved in both early and late stages of hepatocarcinogenesis.

Animals↗
PubMed1991

Improvement of in vitro fertilization and early embryo development in mice by coculture with human fallopian tube epithelium.

Coculturing one- and two-cell embryos with various cell lines has been shown to overcome species-specific developmental blocks and to improve blastocyst transformation rates. The objective of this study was to assess whether human fallopian tube epithelium organ explants influence in vitro fertilization and subsequent early embryo development in a murine model. Fertilization, blastocyst transformation, and blastocyst expansion and hatching rates were significantly higher in the coculture group when compared with rates for culture in standard media or media conditioned by human tubal explant cultures. The results from conditioned and unconditioned media were not significantly different.

Animals↗
PubMed1981

Plasmid transformation of Streptococcus sanguis (Challis) occurs by circular and linear molecules.

Transformation of Streptococcus sanguis (Challis) by antibiotic resistance plasmids has shown that (a) competence developed with identical kinetics for chromosomal and plasmid DNA; (b) dependence of transformant yield on plasmid DNA concentration was second order; (c) open circular plasmid DNA transformed Challis, although at reduced frequency, (d) linearization of plasmid DNA by restriction enzymes cutting at unique sites inactivated the transforming capacity; (e) transforming activity was restored when linear plasmid molecules generated by different restriction enzymes were mixed; (f) restoration of transforming activity depended on the distance between the linearizing cuts, i.e. on the presence of sufficiently long overlapping homologous sequences; (g) when linear deletion mutants were mixed with linear parental plasmids the smaller plasmid was restored with significantly higher frequency. Based on these data, a model for plasmid transformation of Challis is proposed according to which circular plasmid is linearized during binding and uptake. One DNA strand enters the cell and restoration of circular plasmids inside the cell occurs by annealing of complementary single strands from two different donor molecules. Implications of this model for recombinant DNA experiments in streptococci are discussed.

Chromosomes, Bacterial↗
PubMed1997

Model discrimination and estimation of the intraparticle mass transfer parameters for the adsorption of bovine serum albumin onto porous adsorbent particles by the use of experimental frontal analysis data.

Experimental data from a chromatographic system involving the adsorption of bovine serum albumin (BSA) onto porous anion-exchange adsorbent particles packed in a column are presented. The parameters that characterize the mass transfer mechanisms of intraparticle diffusion and convection are estimated by fitting the predictions of dynamic mathematical models describing adsorption in column systems having spherical perfusive and purely diffusive adsorbent particles to the experimental breakthrough data obtained from the column adsorption system. Both linear and nonlinear expressions for the equilibrium isotherm are considered. The values of the transport parameters are estimated in the time domain for the nonlinear adsorption models and in the Laplace transform domain for the linear adsorption models. The capabilities of the different models to describe satisfactorily the dynamic behavior of the adsorption system are compared. The dynamic nonlinear adsorption model for purely diffusive particles is found to describe most appropriately the dynamic behavior of the experimental chromatographic system studied in this work.

Adsorption↗
PubMed1983

Rate theory models for ion transport through rigid pores. III. Continuum vs discrete models in single file diffusion.

In studying the single file model in its discrete as well as in its continuum form the relationship between the phenomenological continuum theory of diffusion and the rate theory approach is analyzed. The single file model in its original form is discrete and represents the most general rate theory model for ion transport through rigid pores in biological membranes. In neglecting the interionic interactions which the single file model takes into account, the Nernst-Planck equation of macroscopic free diffusion can be derived from single file by means of the procedure n leads to infinity (where n is the number of binding sites within a pore) and the classical diffusion theory can thereby be integrated into the more general concept of single filing transport. Moreover, the single file model has been transformed in the limit n leads to infinity into the corresponding continuum form involving interionic interactions. The essential differences between the two derived continuum forms are: In the macroscopic diffusion model, the interionic interactions are regarded in the form of a "mean field". Thus we only get one equation of motion (Nernst-Planck equation) for the ionic concentration c(x, t) within the membrane. In the continuum version of the single file model, however, we obtain a hierarchy of Fokker-Planck equations for the probability density functions Pm(x1, . . . , xm, t) (where m is the number of ions within a pore). The interactions of the single file system are incorporated in detail into the Fokker-Planck equation as well as into the corresponding boundary conditions. As a consequence, the boundary conditions are highly complex in comparison with periodic conditions or Dirichlet conditions often used for the Nernst-Planck equation in electrophysiology. Two types of boundary conditions have been found which are principally different: The first one is to regulate the entry and exit of the ions at the pore mouth by a negative feedback mechanism, the second one describes the collisions of the ions within multiply occupied pores. In this context the question is discussed of whether the continuum version of single file has advantages over the discrete one.

Binding Sites↗
PubMed2006

Comparison of two indices of exposure to polycyclic aromatic hydrocarbons in a retrospective aluminium smelter cohort.

BACKGROUND: The association between coal tar-derived substances, a complex mixture of polycyclic aromatic hydrocarbons, and cancer is well established. However, the specific aetiological agents are unknown. OBJECTIVE: To compare the dose-response relationships for two common measures of coal tar-derived substances, benzene-soluble material (BSM) and benzo(a)pyrene (BaP), and to evaluate which among these is more strongly related to the health outcomes. METHODS: The study population consisted of 6423 men with > or =3 years of work experience at an aluminium smelter (1954-97). Three health outcomes identified from national mortality and cancer databases were evaluated: incidence of bladder cancer (n = 90), incidence of lung cancer (n = 147) and mortality due to acute myocardial infarction (AMI, n = 184). The shape, magnitude and precision of the dose-response relationships and cumulative exposure levels for BSM and BaP were evaluated. Two model structures were assessed, where 1n(relative risk) increased with cumulative exposure (log-linear model) or with log-transformed cumulative exposure (log-log model). RESULTS: The BaP and BSM cumulative exposure metrics were highly correlated (r = 0.94). The increase in model precision using BaP over BSM was 14% for bladder cancer and 5% for lung cancer; no difference was observed for AMI. The log-linear BaP model provided the best fit for bladder cancer. The log-log dose-response models, where risk of disease plateaus at high exposure levels, were the best-fitting models for lung cancer and AMI. CONCLUSION: BaP and BSM were both strongly associated with bladder and lung cancer and modestly associated with AMI. Similar conclusions regarding the associations could be made regardless of the exposure metric.

Air Pollutants, Occupational↗