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PubMed2006

Binding analysis of glycyrrhetinic acid to human serum albumin: fluorescence spectroscopy, FTIR, and molecular modeling.

Fluorescence spectroscopy, Fourier transform infrared spectroscopy (FTIR), and molecular modeling methods were employed to analyze the binding of glycyrrhetinic acid (GEA) to human serum albumin (HSA) under physiological conditions with GEA concentrations from 4.0x10(-6) to 4.5x10(-5) mol L(-1). The binding of GEA to HSA was via two types of sites: the numbers of binding site for the first type was near 0.45 and for the second type it was approximately 0.75. The binding constants of the second type binding site were lower than those of the first type binding site at corresponding temperatures, the results suggesting that the first type of binding site had high affinity and the second binding site involved other sites with lower binding affinity and selectivity. The fluorescence titration results indicated that GEA quenched the fluorescence intensity of HSA through static mechanism. The FTIR spectra evidence showed that the protein secondary structure changed with reduction of alpha-helices about 26.2% at the drug to protein molar ratio of 3. Thermodynamic analysis showed that hydrogen bonds were the mainly binding force in the first type of binding site, and hydrophobic interactions might play a main role in the second type of binding site. Furthermore, the study of computational modeling indicated that GEA could bind to the site I of HSA and hydrophobic interaction was the major acting force for the second type of binding site, which was in agreement with the thermodynamic analysis.

Glycyrrhetinic Acid↗
PubMed1999

A Mental Space Similarity Group Model of Shape Constancy.

A group model of mental transformations based on the geometric model of P. B. Yale (1968, Geometry and symmetry, Holden-Day, San Francisco) was constructed for form recognition. The model consisted of nine characteristic subgroups of the similarity group in Euclidean space. With these subgroups, six series were formed, representing six visual paths for form recognition. Each series involved five characteristic subgroups. Six subframes were associated with nine characteristic subgroups in the model. These subframes were shape (angle measure), the sense, size (volume), verticality, uprightness, and position. The model was validated by an experiment, using reaction time as the behavior index. Since shape is the common invariant property of all subgroups of the similarity group, angle measure was not included in ordering of subframes. The findings show that the preservation of uprightness of a form provides the best condition for form recognition, followed by the preservation of sense and verticality of a form. While the effect of position is not strong, size has the weakest influence on space form recognition. Copyright 1999 Academic Press.

Journal Article↗
PubMed1993

Antimicrobial specificity and hemolytic activity of cyclized basic amphiphilic beta-structural model peptides and their interactions with phospholipid bilayers.

We synthesized a series of cyclic antiparallel beta-sheet model peptides with various ring sizes, which were designed on the basis of a cyclic beta-structural antibiotic, gramicidin S (GS); cyclo(Val-Orn-Leu-D-Phe-Pro)2, and investigated in terms of their antimicrobial activity and specificity against Gram-positive and Gram-negative bacteria and lytic activity for human erythrocytes. In our planning, in order to compare the peptides with GS, D-Phe-Pro sequence forming beta-turn in GS molecule remained unaltered and repeating sequences of alternately hydrophobic (Leu)-hydrophilic (Orn) residue were introduced into the beta-structural parts. CD study in acidic liposomes as well as leakage study of carboxyfluorescein encapsulated in phospholipid vesicles indicated that the peptides strongly interacted with lipid bilayers by taking an amphiphilic beta-structure. Antimicrobial study showed that although GS is active only against Gram-positive bacteria, the antimicrobial spectra of the model peptides transformed gradually to be active against Gram-negative ones and finally only against Gram-negative bacteria whose repeating sequences increased. It should be noted that the designed cyclic model peptides show antibacterial activity but accompany no hemolysis. This indicates that an appropriate hydrophobicity together with a proper orientation of hydrophilic (cationic) and hydrophobic groups in cyclic beta-structural molecules can hold antimicrobial activity against both types of bacteria without damaging eukaryotic cells.

Amino Acid Sequence↗
PubMed1988

SV40 large tumor antigen forms a specific complex with the product of the retinoblastoma susceptibility gene.

Monkey cells synthesizing SV40 large T antigen were lysed and the extracts immunoprecipitated with either monoclonal anti-T antibody or monoclonal antibody to p110-114, the product of the retinoblastoma susceptibility gene (Rb). T and p110-114 coprecipitated in each case, implying that the proteins are complexed with each other. Substitution and internal deletion mutants of T that contain structural alterations in a ten residue, transformation-controlling domain failed to complex with p110-114. In contrast, T mutants bearing structural changes outside of this domain bound to p110-114. These results are consistent with a model for transformation by SV40 which, at least in part, involves T/p110-114 complex formation and the perturbation of Rb protein and/or T function.

Animals↗
PubMed2005

A distributed parameter identification problem in neuronal cable theory models.

Dendritic and axonal processes of nerve cells, along with the soma itself, have membranes with spatially distributed densities of ionic channels of various kinds. These ionic channels play a major role in characterizing the types of excitable responses expected of the cell type. These densities are usually represented as constant parameters in neural models because of the difficulty in experimentally estimating them. However, through microelectrode measurements and selective ion staining techniques, it is known that ion channels are non-uniformly spatially distributed. This paper presents a non-optimization approach to recovering a single spatially non-uniform ion density through use of temporal data that can be gotten from recording microelectrode measurements at the ends of a neural fiber segment of interest. The numerical approach is first applied to a linear cable model and a transformed version of the linear model that has closed-form solutions. Then the numerical method is shown to be applicable to non-linear nerve models by showing it can recover the potassium conductance in the Morris-Lecar model for barnacle muscle, and recover the spine density in a continuous dendritic spine model by Baer and Rinzel.

Action Potentials↗
PubMed2004

Transformation of positively charged aluminium-species in unstable mixing zones following liming.

Liming is widely used to counteract chronic toxicity of positively charged monomeric aluminium species (Ali). Immediately after liming, unstable mixing zones are formed due to the sudden increase in pH. Transformation of monomeric Ali species takes place instantaneously and transient positively charged Al polymers, being acute toxic to fish, are formed in the mixing zones. Using in situ hollow fibre ultrafiltration interfaced with ion chromatography in unstable mixing zone field experiments performed in two river systems situated south and southwest of Norway, information on time-dependent transformations of low molecular mass (LMM) and high molecular mass (HMM) positively charged Ali-species has been followed. The formation of HMM Ali species from LMM Ali occurred rapidly following liming. HMM Ali species have a certain lifetime and are transformed to high molecular mass neutral Al-species (HMM Alo) and then to non-reactive colloidal Al species (HMM Alc). Concentration levels of transient Al-species formed in the mixing zone and the rate of transformation depend on the concentrations of LMM Ali species, Al complexing ligands (DOC and Si) in the input water and on pH in the mixing zone after liming. A dynamic model describing transformation processes influencing the Al speciation in mixing zones following a sudden increase in pH is suggested. Based on the experimental results, associated rate constants and half-lives for transient Al-species were estimated.

Journal Article↗
PubMed1969

Statistical-mechanical studies of the alpha-beta transformation in keratin. IV. The Hill model.

The relationship between the two-dimensional Hill model and the David-Schor extension of the one-dimensional Zimm-Bragg model for the alpha right arrow over left arrow beta transformation in keratins is developed. On the basis of the assumptions of the David Schor model, it appears unlikely that the Hill model in its present form can give detailed agreement with the experimental tension-length isotherms.

Keratins↗
PubMed2005

Malignant transformation of thymoma in recipient rats by heterotopic thymus transplantation from HTLV-I transgenic rats.

Transgenic rats expressing the pX gene of human T lymphocyte virus type-I (HTLV-I) under control of the rat lymphocyte-specific protein tyrosine kinase type-I promoter (lck-pX rats) developed benign epithelial thymomas. When the thymuses of newborn lck-pX rats were transplanted into the subcapsular space of the kidney in other thymectomized lck-pX rats, similar tumors developed in the transplanted thymuses. Following the tumor growth, dissemination in the abdominal cavity and distant metastasis occurred. The tumors were histopathologically similar to the original thymomas, but prominent nuclear atypia and high mitotic activity were present. The Ki-67 index was twice as high as that in the originals. The tumors were transplantable into the subcutis of lck-pX rats, although transplantation of the originals never succeeded. All evidence indicated that malignant transformation of thymoma was induced by the heterotopic transplantation. Expression of the pX transgene in the transformed tumors were significantly reduced. Among host genes, the expression of p16ink4a/ARF, which was significantly upregulated in the originals, was never detected in the transformed tumors. Genomic Southern blots and PCR suggest that homozygous deletion of the p16ink4a/ARF gene may play important roles in malignant transformation in this model. Our model described here is a useful unique model for in vivo malignant transformation.

Animals↗
PubMed1998

A unified theory of carcinogenesis based on order-disorder transitions in DNA structure as studied in the human ovary and breast.

Fourier transform-infrared/statistics models demonstrate that the malignant transformation of morphologically normal human ovarian and breast tissues involves the creation of a high degree of structural modification (disorder) in DNA, before restoration of order in distant metastases. Order-disorder transitions were revealed by methods including principal components analysis of infrared spectra in which DNA samples were represented by points in two-dimensional space. Differences between the geometric sizes of clusters of points and between their locations revealed the magnitude of the order-disorder transitions. Infrared spectra provided evidence for the types of structural changes involved. Normal ovarian DNAs formed a tight cluster comparable to that of normal human blood leukocytes. The DNAs of ovarian primary carcinomas, including those that had given rise to metastases, had a high degree of disorder, whereas the DNAs of distant metastases from ovarian carcinomas were relatively ordered. However, the spectra of the metastases were more diverse than those of normal ovarian DNAs in regions assigned to base vibrations, implying increased genetic changes. DNAs of normal female breasts were substantially disordered (e.g., compared with the human blood leukocytes) as were those of the primary carcinomas, whether or not they had metastasized. The DNAs of distant breast cancer metastases were relatively ordered. These findings evoke a unified theory of carcinogenesis in which the creation of disorder in the DNA structure is an obligatory process followed by the selection of ordered, mutated DNA forms that ultimately give rise to metastases.

Adenocarcinoma↗
PubMed2003

Analytical solutions to compartmental indoor air quality models with application to environmental tobacco smoke concentrations measured in a house.

This paper derives the analytical solutions to multi-compartment indoor air quality models for predicting indoor air pollutant concentrations in the home and evaluates the solutions using experimental measurements in the rooms of a single-story residence. The model uses Laplace transform methods to solve the mass balance equations for two interconnected compartments, obtaining analytical solutions that can be applied without a computer. Environmental tobacco smoke (ETS) sources such as the cigarette typically emit pollutants for relatively short times (7-11 min) and are represented mathematically by a "rectangular" source emission time function, or approximated by a short-duration source called an "impulse" time function. Other time-varying indoor sources also can be represented by Laplace transforms. The two-compartment model is more complicated than the single-compartment model and has more parameters, including the cigarette or combustion source emission rate as a function of time, room volumes, compartmental air change rates, and interzonal air flow factors expressed as dimensionless ratios. This paper provides analytical solutions for the impulse, step (Heaviside), and rectangular source emission time functions. It evaluates the indoor model in an unoccupied two-bedroom home using cigars and cigarettes as sources with continuous measurements of carbon monoxide (CO), respirable suspended particles (RSP), and particulate polycyclic aromatic hydrocarbons (PPAH). Fine particle mass concentrations (RSP or PM3.5) are measured using real-time monitors. In our experiments, simultaneous measurements of concentrations at three heights in a bedroom confirm an important assumption of the model-spatial uniformity of mixing. The parameter values of the two-compartment model were obtained using a "grid search" optimization method, and the predicted solutions agreed well with the measured concentration time series in the rooms of the home. The door and window positions in each room had considerable effect on the pollutant concentrations observed in the home. Because of the small volumes and low air change rates of most homes, indoor pollutant concentrations from smoking activity in a home can be very high and can persist at measurable levels indoors for many hours.

Air Movements↗
PubMed2001

Cadmium-induced cell transformation and tumorigenesis are associated with transcriptional activation of c-fos, c-jun, and c-myc proto-oncogenes: role of cellular calcium and reactive oxygen species.

The molecular mechanisms of carcinogenesis by cadmium were studied using BALB/c-3T3 cell transformation and nude mouse tumorigenesis models. BALB/c-3T3 cells transformed with cadmium chloride were subcutaneously injected into nude mice to develop tumors and the cell lines derived from these tumors were used in the present study. The proto-oncogenes c-fos and c-jun were overexpressed in 100% (10 out of 10) of the cell lines, while a statistically significant overexpression of c-myc was observed in 40% (4 out of 10) of the cell lines. Analysis of tumor cells stained with fluorescent dyes specific for reactive oxygen species revealed that these cells possessed markedly higher levels of superoxide anion and hydrogen peroxide compared with the nontransformed cells. Similarly, the intracellular calcium level was higher in the tumor cells compared with the nontransformed cells. Overexpression of the proto-oncogenes in these cells was blocked by treating the cells with superoxide dismutase, catalase, and 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetra acetoxy methyl ester (BAPTA/AM), which are scavengers of superoxide anion, hydrogen peroxide, and calcium, respectively. This confirmed that the overexpression of the proto-oncogenes in the tumor cells required elevated intracellular levels of reactive oxygen species and calcium. In addition to the scavengers of reactive oxygen species and calcium, inhibitors specific for transcription (actinomycin D), protein kinase C (RO-31-8220), and MAP kinase (PD 98059) also blocked the cadmium-induced overexpression of the proto-oncogenes in the tumor cells. Exposure of the nontransformed BALB/c-3T3 cells to 20 microM cadmium chloride for 1 h caused elevated intracellular levels of superoxide anion, hydrogen peroxide, and calcium, with corresponding increases in the expression levels of c-fos, c-jun, and c-myc. As in the case of the tumor cells, treating the nontransformed cells with the various modulators prior to their exposure to cadmium chloride resulted in inhibition in the expression of the proto-oncogenes. Based on these data, we conclude that the cadmium-induced overexpression of cellular proto-oncogenes is mediated by the elevation of intracellular levels of superoxide anion, hydrogen peroxide, and calcium. Further, the cadmium-induced overexpression of the proto-oncogenes is dependent on transcriptional activation as well as on pathways involving protein kinase C and MAP kinase.

3T3 Cells↗
PubMed1977

Quadratic analyses of reciprocal crosses.

Three different models, a two-way factorial model for familiarity, an orthogonalizing transform of this model to a diallel model, and a bio model more representative of the biological situation, are interrelated in terms of their components of variance and covariance. It is clarified that there are five components that can be reckoned with in the analysis of reciprocal crosses, including distinct maternal and paternal variances. Estimation of the components and tests of hypotheses concerning them are outlined for two types of mating designs with reciprocals. One deisgn involves a factorial mating design between two distinct sets of parents or parental lines and the other a diallel of all crosses from a single set of parents or parental lines. Both designs provide the same types of information and similar tests of hypotheses. At least some parts of the analyses corresponding to the factorial model are required to separate the maternal and paternal variances. A least squares partitioning of the sums of squares according to the diallel model, but with expectations expressed in terms of the bio model, provides most of the tests of hypotheses of interest. Worked examples are given.

Crosses, Genetic↗
PubMed1996

[Homology and evolution of gene order: a simple method for testing a hypothesis on the nature of this evolution].

A method of testing various hypotheses concerning the mechanisms of evolution of gene order is suggested. Estimating the possibility of constructing an evolutionary tree that reflects the observed similarity between gene orders studied is proposed, provided that the distances between gene orders correspond to estimations obtained on the basis of the hypothesis tested. The required IBM PC software was developed. It was found that gene orders of the mouse, rabbit, cow, cat, lemur, capuchin monkey, rhesus monkey, gorilla, chimpanzee, and man could be readily interpreted in terms of the simplest ("map") model of transformation of these orders.

Animals↗
PubMed2003

Up-regulation of hepatocyte growth factor caused by an over-expression of transforming growth factor beta, in the rat model of fulminant hepatic failure.

BACKGROUND: The role of transforming growth factor beta (TGF-beta), a potent regulator of cellular growth, was investigated in the rat model of fulminant hepatic failure (FHF). MATERIALS AND METHODS: The rat FHF model was created by a combination of a 68% partial hepatectomy (PH) and 7% of necrosis (each n = 25 in Groups 1, 2 and 3). Adenovirus mediated gene transfer of mature human TGF-beta1 gene was performed by the systemic injection of AxCAhTGFb1 (1 x 10(9) pfu) in Group 1, 3 days before FHF. In control Groups 2 and 3, recombinant lacZ adenovirus (AxCAlacZ, Group 2) and normal saline (1 ml, Group 3) were used, instead of AxCAhTGFb1. RESULTS: An excessive expression of TGF-beta1 in Group 1 resulted in an inhibition of hepatocyte proliferation (24-48 h after FHF) and gaining of liver weight (24-48 h), increased expression of HGF in liver tissue (24 h), and decreased expression of TGF-alpha (24 h), compared to those in control Groups 2 and 3. Serum IL-6 levels were also elevated by a TGF-beta1 over-expression at 24 hrs after FHF in Group 1. CONCLUSIONS: The forced expression of TGF-beta1 in the FHF liver yields both a secondary increase of HGF production and a suppression of liver regeneration, which might explain the mechanism of increased serum HGF observed in a clinical FHF. TGF-beta1 is thus thought to have an important role in inhibiting liver regeneration after FHF.

Adenoviridae↗
PubMed2004

Ectopic expression of the homeobox gene Cdx2 is the transforming event in a mouse model of t(12;13)(p13;q12) acute myeloid leukemia.

Creation of fusion genes by balanced chromosomal translocations is one of the hallmarks of acute myeloid leukemia (AML) and is considered one of the key leukemogenic events in this disease. In t(12;13)(p13;q12) AML, ectopic expression of the homeobox gene CDX2 was detected in addition to expression of the ETV6-CDX2 fusion gene, generated by the chromosomal translocation. Here we show in a murine model of t(12;13)(p13;q12) AML that myeloid leukemogenesis is induced by the ectopic expression of CDX2 and not by the ETV6-CDX2 chimeric gene. Mice transplanted with bone marrow cells retrovirally engineered to express Cdx2 rapidly succumbed to fatal and transplantable AML. The transforming capacity of Cdx2 depended on an intact homeodomain and the N-terminal transactivation domain. Transplantation of bone marrow cells expressing ETV6-CDX2 failed to induce leukemia. Furthermore, coexpression of ETV6-CDX2 and Cdx2 in bone marrow cells did not accelerate the course of disease in transplanted mice compared to Cdx2 alone. These data demonstrate that activation of a protooncogene by a balanced chromosomal translocation can be the pivotal leukemogenic event in AML, characterized by the expression of a leukemia-specific fusion gene. Furthermore, these findings link protooncogene activation to myeloid leukemogenesis, an oncogenic mechanism so far associated mainly with lymphoid leukemias and lymphomas.

Animals↗
PubMed2000

High plasma concentrations of prorenin in a transgenic animal model of nephropathy with overexpression of transforming growth factor-beta1 in the kidneys.

1. Plasma concentrations of prorenin were determined in a transgenic animal model of nephropathy induced by overexpression of transforming growth factor (TGF)-beta1 in the juxtaglomerular apparatus. 2. In both female and male mice, plasma concentrations of prorenin were higher in transgenic than in non-transgenic animals. In sexually mature mice, plasma prorenin concentrations were higher in males than in females in both transgenic and non-transgenic animals in accordance with a sexual dimorphism of the plasma concentration of prorenin. 3. The results indicate that TGF-beta1-like androgens increase prorenin secretion in the kidneys and may explain the increased plasma prorenin concentrations in patients with diabetic nephropathy.

Aging↗
PubMed1998

Combination of transforming growth factor beta antisense and interleukin-2 gene therapy in the murine ovarian teratoma model.

The immunosuppressive protein transforming growth factor beta (TGF-beta) inhibits the activation of various immune effector cells including cytotoxic T lymphocytes and may therefore inhibit the efficacy of immunostimulatory interleukin-2 (IL-2) gene therapy. In this study, we investigated the effect of TGF-beta downregulation on IL-2 gene therapy in the intraperitoneal model of murine ovarian teratoma (MOT). MOT cells, like many human ovarian carcinomas, were found to produce TGF-beta. Production of TGF-beta by MOT cells was suppressed using a TGF-beta antisense plasmid vector (pCEP4/TGF-beta antisense). Subcutaneous immunization of C3H mice with a mixture of IL-2 gene-transduced fibroblasts and TGF-beta antisense-modified MOT cells induced significantly better protection against a subsequent intraperitoneal tumor challenge compared with immunization with unmodified MOT cells alone [11/16 (69%) vs 4/21 (19%) tumor-free animals, P < 0.01]. Immunization with either a mixture of IL-2 gene modified fibroblasts and unmodified MOT cells [2/12 (17%) tumor-free animals] or TGF-beta antisense-modified MOT cells alone (0/13 tumor free animals) failed to induce significant protection compared with immunization with unmodified MOT cells. These data show that combined TGF-beta antisense and IL-2 gene therapy is required to generate effective antitumor responses in the MOT model. Our findings suggest that tumor cell expression of immunosuppressive factors may inhibit cytokine immunogene therapy and may have potential implications for the development of future clinical immunogene therapy protocols.

3T3 Cells↗
PubMed2003

Genomic Object Net: I. A platform for modelling and simulating biopathways.

Genomic Object Net (GON) 1.0 is a software package for creating models and simulations of biopathways. Its core architecture employs the notion of a hybrid functional Petri net with extension (HFPNe). HFPNe can seamlessly handle discrete and continuous objects and events while keeping the model components themselves simple. With the feature and graphical model editor, biopathways can be modelled intuitively and simulated on GON. The subsequent output of the simulation results can be evaluated in customised views on GON Visualizer by writing an XML file. Additionally, GON provides a tool to transform biopathway models in KEGG and BioCyc to the GON XML files for modelling and simulation. The tool avoids a lot of tedious work by users, enabling them to focus on the biological model.

Cell Physiological Phenomena↗