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At least 793 records · Page 44Linked to original sources
PubMed2003

TGF-beta1-mediated fibroblast-myofibroblast terminal differentiation-the role of Smad proteins.

It is now clear that resident myofibroblasts play a central role in the mediation of tissue fibrosis. The aim of the work outlined in this study is to increase our understanding of the mechanisms which drive the phenotypic and functional changes associated with the differentiation process. We have used an in vitro model of transforming growth factor-beta1 (TGF-beta1)-induced pulmonary fibroblast-myofibroblast differentiation to examine the role of the TGF-beta1 Smad protein signaling intermediates, in alterations of fibroblast phenotype and function associated with terminal differentiation. TGF-beta1 induced marked alteration in cell phenotype, such that cells resembled "epithelioid-postmitotic fibroblasts." This was associated with marked reorganization of the actin cytoskeleton and upregulation of alphaSMA gene expression. TGF-beta1 stimulation also induced alphaSMA protein expression with increased incorporation of alphaSMA into stress fibers. Following stimulation with TGF-beta1, subsequent addition of serum-free medium did not reverse TGF-beta1-induced morphological change, suggesting that TGF-beta1 induced a relatively stable alteration in fibroblast cell phenotype. Functionally, these phenotypic changes were associated with induction of type I, type III, and type IV collagen gene expression and an increase in the concentrations of the respective collagens in the cell culture supernatant. The role of Smad proteins in terminal differentiation of fibroblasts was examined by transfection of cells, with expression vectors for the TGFbeta1 receptor-regulated Smads (R-Smads) or the co-Smad, Smad 4. Transfection with Smad2 but not Smad3 resulted in TGF-beta1 independent alteration in fibroblast cell phenotype, up-regulation of alphaSMA mRNA and reorganization of the actin cytoskeleton. Transfection with Smad4 also induced alteration in cell phenotype, although this was not as pronounced as the effect of overexpression of Smad2. Overexpression of the Smad2, Smad3, or Smad4 proteins was associated with increased production of all collagen types. The study suggests that the phenotypic and functional changes associated with TGF-beta1-induced fibroblast terminal differentiation are differentially regulated by Smad proteins.

Actins↗
PubMed1999

A single-chain antibody fragment specific for the Plasmodium berghei ookinete protein Pbs21 confers transmission blockade in the mosquito midgut.

Mouse monoclonal antibody 13.1 (mAb 13.1) directed against Pbs21, a 21-kDa sexual-stage surface protein of Plasmodium berghei, is known to inhibit oocyst development from gametocytes and ookinetes in the mosquito midgut. To examine the properties and potential uses of a single-chain antibody fragment (scFv) for blocking transmission of malaria parasites to mosquitoes, we have cloned and sequenced the genes encoding variable regions of the immunoglobulin heavy and light chains (V(H) and V(L)) of mAb 13.1. The V(H) and V(L) genes were assembled as an scFv gene, and expressed in a baculovirus expression system. Following purification of 13.1 scFv, Western blotting and inhibition ELISA assays confirmed that 13.1 scFv retained the binding specificity of the parent mAb 13.1 for Pbs21. Furthermore, 13.1 scFv bound to the surface of P. berghei ookinetes, and blocked oocyst development in the mosquito midgut by at least 93%, as assessed by oocyst counts in mosquitoes. We suggest that the 13.1 scFv gene could be useful not only in studying the mechanism of transmission blockade, but also in generating, by mosquito germline transformation, a model system to evaluate the production of mosquitoes refractory to malaria.

Amino Acid Sequence↗
PubMed1999

Microbial models of drug metabolism: microbial transformations of Trimegestone (RU27987), a 3-keto-delta(4,9(10))-19-norsteroid drug.

Screening microorganisms for the biotransformation of the 3-keto-delta(4,9(10))-19-norsteroid RU27987 (Trimegestone) resulted in the isolation of nine identified metabolites, some of them being selectively produced by different strains. Eight metabolites were found to be hydroxylated on various positions of the rings, and one was additionally epoxidized. These microbial metabolites could be used as chromatographic standards and two of them were found identical to the unknown major human metabolites. Moreover, most microbial metabolites were produced in sufficient amounts to be tested for their biological activities. All these features demonstrate the usefulness and versatility of microbial biotransformation systems as a tool for early identification and convenient production of potentially active mammalian and non-mammalian metabolites.

Biotransformation↗
PubMed2004

Environmental remediation by an integrated microwave/UV illumination technique. 8. Fate of carboxylic acids, aldehydes, alkoxycarbonyl and phenolic substrates in a microwave radiation field in the presence of TiO2 particles under UV irradiation.

Thermal and nonthermal effects originating when a system is subjected to a microwave radiation field in the TiO2-photocatalyzed transformation of model substances containing various functional groups (e.g., benzoic acid, phthalic acid, o-formylbenzoic acid, phthalaldehyde, succinic acid, dimethyl phthalate, diethyl phthalate, and phenol) have been examined under simultaneous irradiation by ultraviolet (UV) and microwave (MW) radiations. Characteristics of the microwave effects and the fate of each substrate during the microwave-assisted photocatalytic process were monitored by UV absorption spectroscopy, HPLC methods, total organic carbon assays, and identification of intermediates using electrospray mass spectral techniques. Microwave thermal and nonthermal effects were delineated by comparing results from MW-generated internal heat versus conventional external heating, and at constant ambient temperature under a microwave field. Factors involved in the nonthermal component of the microwave radiation were inferred for the initial adsorption of the substrate and its subsequent degradation occurring on the surface of TiO2 particles. Microwave effects bear on the mechanism through which a model substrate undergoes oxidative degradation. A characteristic feature of these effects was briefly examined by considering the behavior of polar (dipole moments) substrates in a microwave radiation field.

Aldehydes↗
PubMed2004

Radical generation by the interaction of transition metals with common oxidants.

Nine transition metals were tested for the activation of three oxidants and the generation of inorganic radical species such as sulfate, peroxymonosulfate, and hydroxyl radicals. From the 27 combinations, 14 M/Ox couples demonstrated significant reactivity toward transforming a model organic substrate such as 2,4-dichlorophenol and are further discussed here. It was found that Co(II) and Ru(III) are the best metal catalysts for the activation of peroxymonosulfate. As expected on the basis of the Fenton reagent, Fe(III) and Fe(II) were the most efficient transition metals for the activation of hydrogen peroxide. Finally, Ag(I) showed the best results toward activating persulfate. Quenching studies with specific alcohols (tert-butyl alcohol and ethanol) were also performed to identify the primary radical species formed from the reactive M/Ox interactions. The determination of these transient species allowed us to postulate the rate-determining step of the redox reactions taking place when a metal is coupled with an oxidant in aqueous solution. It was found that when Co(II), Ru(III), and Fe(II) interact with peroxymonosulfate, freely diffusible sulfate radicals are the primary species formed. The same was proven for the interaction of Ag(I) with persulfate, but in this case caged or bound to the metal sulfate radicals might be formed as well. The conjunction of Ce(III), Mn(II), and Ni(II) with peroxymonosulfate showed also to generate caged or bound to the metal sulfate radicals. A combination of sulfate and hydroxyl radicals was formed from the conjunction of V(III) with peroxymonosulfate and from Fe(II) with persulfate. Finally, the conjunction of Fe(III), Fe(II), and Ru(III) with hydrogen peroxide led primarily to the generation of hydroxyl radicals. It is also suggested here that the redox behavior of a particular metal in solution cannot be predicted based exclusively on its size and charge. Additional phenomena such as metal hydrolysis as well as complexation with other counterions present in solution might affect the thermodynamics of the overall process and are further discussed here.

Catalysis↗
PubMed2005

Size-dependent phase transformation kinetics in nanocrystalline ZnS.

Nanocrystalline ZnS was coarsened under hydrothermal conditions to investigate the effect of particle size on phase transformation kinetics. Although bulk wurtzite is metastable relative to sphalerite below 1020 degrees C at low pressure, sphalerite transforms to wurtzite at 225 degrees C in the hydrothermal experiments. This indicates that nanocrystalline wurtzite is stable at low temperature. High-resolution transmission electron microscope data indicate there are no pure wurtzite particles in the coarsened samples and that wurtzite only grows on the surface of coarsened sphalerite particles. Crystal growth of wurtzite stops when the diameter of the sphalerite-wurtzite interface reaches approximately 22 nm. We infer that crystal growth of wurtzite is kinetically controlled by the radius of the sphalerite-wurtzite interface. A new phase transformation kinetic model based on collective movement of atoms across the interface is developed to explain the experimental results.

Journal Article↗
PubMed2006

Pulsed electrodeposition of two-dimensional Ag nanostructures on Au(111).

One-step pulsed potential electrodeposition of Ag on Au(111) in the underpotential deposition (UPD) region has been studied in 0.5 mM Ag2SO4 + 0.1 M H2SO4 aqueous electrolyte at various pulse durations from 0.2 to 500 ms. Evolution of the deposited Ag nanostructures was followed by in situ scanning tunneling microscopy (STM) and by measurement of the respective current transients. At short pulse durations a relatively high number density (4 x 10(11) cm(-2)) of two-dimensional Ag clusters with a narrow size and distance distribution is observed. They exhibit a remarkably high stability characterized by a dissolution potential which lies about 200 mV more anodically than the typical potential of Ag-(1 x 1) monolayer dissolution. To elucidate the underlying nucleation and growth mechanism, two models have been considered: two-dimensional lattice incorporation and a newly developed coupled diffusion-adsorption model. The first one yields a qualitative description of the current transients, whereas the second one is in nearly quantitative agreement with the experimental data. In this model the transformation of a Ag-(3 x 3) into a Ag-(1 x 1) structure indicated in the cyclic voltammogram (peaks at 520 vs 20 mV) is taken into account.

Journal Article↗
PubMed1988

Leprosy and immunity: genetics and immune function in multiple case families.

Genetic susceptibility to infection with M. leprae was studied in 10 multiple case families of Australian Aborigines. Of the 87 members available for study, 24 had proven stable clinical leprosy which had been or was still being treated with diamino diphenyl sulphone. Evidence of contact with M. leprae in the remaining 63 members as assessed by ELISA to M. leprae sonicate and phenolic glycolipid (PGL) or by indirect immunofluorescence antibody assay was found in 78%, 64% and 71%, respectively. By contrast, in vitro assays of T cell function (LMAT and LTT) were less reliable indicators of exposure. Evidence was sought for possible linkages between human leucocyte antigen (HLA) or non-HLA genes and four marker phenotypes including clinical leprosy, clinical subtype of leprosy and lymphocyte transformation or leucocyte migration inhibition factor (LIF) production in response to M. leprae antigen. No associations were found with any particular HLA or non-HLA gene. On the other hand, sequential analysis of the data from the 10 families was strongly suggestive of a linkage between HLA haplotype and non-responsiveness to M. leprae as manifest by lack of LIF production but not lymphocyte transformation. The model which best fits the data is for a gene on chromosome 6 in close linkage with the HLA haplotype, with two alleles, autosomal recessive inheritance and penetrance of 90%. On this basis, it can be suggested that disease type (lepromatous leprosy) rather than disease susceptibility may be controlled by genes within or closely linked to the major histocompatibility gene complex.

Antigens, Bacterial↗
PubMed2006

Induction of tetraploidy through loss of p53 and upregulation of Plk1 by human papillomavirus type-16 E6.

Cancer cells are insensitive to many signals that inhibit growth of untransformed cells. Here, we show that primary human epithelial cells expressing human papillomavirus (HPV) type-16 E6/E7 bypass arrest caused by the DNA-damaging drug adriamycin and become tetraploid. To determine the contribution of E6 in the context of E7 to the resistance of arrest and induction of tetraploidy, we used an E6 mutant unable to degrade p53 or RNAi targeting p53 for knockdown. The E6 mutant fails to generate tetraploidy; however, the presence of E7 is sufficient to bypass arrest while the p53 RNAi permits both arrest insensitivity and tetraploidy. We published previously that polo-like kinase 1 (Plk1) is upregulated in E6/E7-expressing cells. We observe here that abnormal expression of Plk1 protein correlates with tetraploidy. Using the p53 binding-defective mutant of E6 and p53 RNAi, we show that p53 represses Plk1, suggesting that loss of p53 results in tetraploidy through upregulation of Plk1. Consistent with this hypothesis, overexpression of Plk1 in cells generates tetraploidy but does not confer resistance to arrest. These results support a model for transformation caused by HPV-16 where bypass of arrest and tetraploidy are separable consequences of p53 loss with Plk1 required only for the latter effect.

Cell Cycle Proteins↗
PubMed2003

Essential role of an activator protein-2 (AP-2)/specificity protein 1 (Sp1) cluster in the UVB-mediated induction of the human vascular endothelial growth factor in HaCaT keratinocytes.

Chronic sun exposure of the skin has long been postulated to enhance cutaneous angiogenesis, resulting in highly vascularized skin cancers. As the UVB component of sunlight is a major contributor to photocarcinogenesis, we aimed to explore the effects of UVB radiation on vascular endothelial growth factor (VEGF) gene expression, using the immortalized keratinocyte cell line HaCaT as a model for transformed premalignant epithelial cells. In the present paper, we studied the molecular mechanism of UVB-induced VEGF providing a major angiogenic activity in tumour progression and invasion. After 12-24 h of UVB irradiation, a 2.4- to 2.7-fold increase in endogenous VEGF protein level was measured, correlating with an up to 2.5-fold induction of promoter-based reporter gene constructs of VEGF. Furthermore, we identified a GC-rich UVB-responsive region between -87 and -65 bp of the VEGF promoter. In electrophoretic mobility-shift assays, this region binds Sp1-dependent protein complexes constitutively and an additional UVB-inducible protein complex distinct from Sp1 protein. The transcription factor AP-2 (activator protein-2) was detected as a component of the UVB-inducible protein complex. The critical role of the AP-2/Sp1 (specificity protein 1) cluster was supported by demonstration of a significant reduction of UVB-mediated promoter activity upon deletion of this recognition site. The specificity of this region for UVB irradiation was demonstrated using PMA, which increased VEGF activity in HaCaT cells after transient transfection of the deleted promoter construct. In conclusion, our data clarified regulatory mechanisms of UVB-dependent VEGF stimulation which may be critical for angiogenic processes in the skin.

Antibiotics, Antineoplastic↗
PubMed1993

Turnover of inositol pentakisphosphates, inositol hexakisphosphate and diphosphoinositol polyphosphates in primary cultured hepatocytes.

We have used a non-transformed cell model, the primary cultured hepatocyte, to explore the turnover of inositol hexakisphosphate, multiple isomers of inositol pentakisphosphate and two novel diphosphoinositol polyphosphates. All of these compounds gradually accumulated radioactivity throughout a 70 h period of labelling with [3H]inositol. However, a rapid metabolic rate was revealed upon inhibition of diphosphoinositol polyphosphate biphosphatase(s) with 1 mM fluoride for 40 min: this treatment elevated levels of [3H]diphosphoinositol polyphosphates up to 10-fold, indicating that their cellular pools were normally turning over at least 10 times every 40 min. This was accompanied by a turnover of about 10% of the pool of inositol hexakisphosphate. Control experiments established that 200 nM vasopressin brought about a typical activation of phospholipase C in hepatocytes after 62 h of primary culture. This agonist treatment did not affect steady-state levels of [3H]inositol pentakisphosphates, [3H]inositol hexakisphosphate or [3H]diphosphoinositol polyphosphates. However, prolonged treatment of hepatocytes with 2 microM thapsigargin reduced steady-state levels of [3H]diphosphoinositol polyphosphates by 50-70%. This effect of thapsigargin was also observed in the presence of fluoride, indicating that thapsigargin inhibited the rate of synthesis of diphosphoinositol polyphosphates.

Cells, Cultured↗
PubMed2002

Measurement of the three-dimensional microscope point spread function using a Shack-Hartmann wavefront sensor.

We present a technique to measure the wavefront in the exit pupil of a microscope to determine the microscope's three-dimensional point spread function (PSF) experimentally. The wavefront yields the microscope PSF through a Fourier transform that models propagation of light from the exit pupil to the image plane. A Shack-Hartmann wavefront sensor is used to measure the wavefront shape by recording lateral displacements of a grid of focused spots created by a lenslet array. The displacement of each spot is related to the local wavefront slope. Thus, with appropriate sampling across the exit pupil, the entire wavefront can be reconstructed. This technique does not require the use of a sub-resolution object to obtain the three-dimensional microscope PSF. Consequently, larger, brighter fluorescent objects may be imaged, thereby reducing the requirements for detector sensitivity and leading to a three-fold increase in the axial range over which the PSF is measured. The Shack-Hartmann technique results in a description of the PSF as a continuous function whose sampling is not dependent on the size of the CCD pixels. The Shack-Hartmann sensor is not limited by the numerical aperture of the objective and can easily be calibrated to measure the PSF at any wavelength.

Image Processing, Computer-Assisted↗
PubMed2006

Crystal structure of human apolipoprotein A-I: insights into its protective effect against cardiovascular diseases.

Despite three decades of extensive studies on human apolipoprotein A-I (apoA-I), the major protein component in high-density lipoproteins, the molecular basis for its antiatherogenic function is elusive, in part because of lack of a structure of the full-length protein. We describe here the crystal structure of lipid-free apoA-I at 2.4 A. The structure shows that apoA-I is comprised of an N-terminal four-helix bundle and two C-terminal helices. The N-terminal domain plays a prominent role in maintaining its lipid-free conformation, indicating that mutants with truncations in this region form inadequate models for explaining functional properties of apoA-I. A model for transformation of the lipid-free conformation to the high-density lipoprotein-bound form follows from an analysis of solvent-accessible hydrophobic patches on the surface of the structure and their proximity to the hydrophobic core of the four-helix bundle. The crystal structure of human apoA-I displays a hitherto-unobserved array of positively and negatively charged areas on the surface. Positioning of the charged surface patches relative to hydrophobic regions near the C terminus of the protein offers insights into its interaction with cell-surface components of the reverse cholesterol transport pathway and antiatherogenic properties of this protein. This structure provides a much-needed structural template for exploration of molecular mechanisms by which human apoA-I ameliorates atherosclerosis and inflammatory diseases.

Apolipoprotein A-I↗
PubMed1984

An immunological method for detecting gene expression in yeast colonies.

A method for detection of cloned, expressed genes in yeast colonies has been developed. The 70-kilodalton (kDa) mitochondrial outer membrane protein of yeast was used as a model protein. Transformation of a strain deficient in the gene for the 70-kDa protein was performed, and transformed colonies were detected with the antibody decoration technique. This technique is based upon gentle lysis of yeast colonies that have been grown on nitrocellulose filters such that the yeast proteins remain bound in discrete spots after lysis. The lysis is carried out by alkaline conditions in the presence of 2-mercaptoethanol and sodium dodecyl sulfate. After lysis, empty sites on the nitrocellulose filter are blocked to eliminate nonspecific binding of proteins by either 0.5% bovine serum albumin or 0.05% Tween 20. Decoration with antibody is visualized by using 125I-labeled protein A or peroxidase-conjugated second antibody. Antigens amounting to less than 0.1% of the total protein in the cell can be readily detected by the assay. The sensitivity of the assay enables detection of 1 positive colony per plate containing about 1000 colonies.

Antigen-Antibody Complex↗
PubMed1966

Integration of deoxyribonuclease-treated DNA in bacillus subtilis transformation.

Normal preparations of B. subtilis DNA have weight average native molecular weights of 10 to 30 x 10(6). For any given preparation the upper and lower 95% size limits may differ by a factor of ten or more. Single-stranded molecular weights indicate an average of 1 to 4 breaks per single strand of the native DNA. The reduction in transforming activity and viscosity following DNAase I digestion can be accounted for by a direct relationship between the transforming activity of a DNA and its single-stranded molecular weight. Uptake studies with DNAase I treated heavy ((2)H(15)N (3)H) DNA show that single strand breaks inhibit integration less than transformation. A provisional estimate of the size of the integrated region based on correlating the single strand size of the donor-recipient complex with the donor-recipient density differences following alkali denaturation came to 1530 nucleotides. Using a competent, nonleaky thymine-requiring strain of B. subtilis grown in 5-BU medium before and after transformation, it was shown that (a) No detectable amount of DNA synthesis is necessary for the initial stages of integration, (b) Cells which have recently been replicating DNA are not competent. (c) Cells containing donor DNA show a lag in DNA replication following transformation, (d) When donor DNA is replicated it initially appears in a density region between light and hybrid. This indicates that it includes the transition point formed at the time of reinitiation of DNA synthesis in the presence of 5-BU following transformation. A model is proposed in which donor DNA is integrated at the stationary growing point of the competent cell, which is in a state of suspended DNA synthesis.

Bacillus subtilis↗
PubMed1988

A modified x-ray spectra reconstruction technique.

We have previously reported on a four-parameter Laplace transform pair model that accurately reconstructs x-ray spectra from attenuation data. However, for some spectra, the model exhibits non-physical characteristics at the higher x-ray energies. This results when one of the fitted parameters, v, is less than or equal to 0.6. Simply limiting the parameter to values greater than 0.6 produces an unsatisfactory result. It is shown that improved accuracy is obtained when the model is applied to a more filtered segment of the attenuation curve. The resulting spectrum is satisfactory for the more filtered beam. One can then reliably construct the original spectrum by mathematically correcting for the additional filtration.

Models, Theoretical↗
PubMed2004

Discrimination models using variance-stabilizing transformation of metabolomic NMR data.

After the extensive work that is being done in the areas of genomics, proteomics, and metabolomics, the study of metabolites has come of interest in its own right. Metabolites in biological systems give an understanding of the state of the system and provide a powerful tool for the study of disease and other maladies. Several analytical techniques such as mass spectrometry and high-resolution NMR spectroscopy have been used to study metabolites. The data, however, from these techniques remains quite complex. Traditionally, multivariate analyses have been used for such data. These methods however have an underlying assumption that the data is multivariate normal with a constant variance. This is not necessarily the case. It has been shown that a generalized log transformation renders the variance of the data constant effectively making the data more suitable for multivariate analysis. We demonstrate the effectiveness of these transformations on NMR data taken on a set of 18 abalone that were categorized as either being healthy, stunted, or diseased. We show how the transformation makes multivariate classification of the abalone into the healthy, stunted and diseased categories much more effective and gives a tool for identifying potential metabolic biomarkers for disease.

Animals↗
PubMed1998

Acetaldehyde alters proliferation, differentiation and adhesion properties of human colon adenocarcinoma cell line Caco-2.

Studies with experimental animals indicate that acetaldehyde, the first metabolite of ethanol that is microbially formed in the colonic lumen, may play a role in ethanol-associated colorectal co-carcinogenesis. Although intracoIonic acetaldehyde concentrations are highest during the metabolism of exogenous ethanol, some individuals may also possess marked amounts of endogenous acetaldehyde. Since no information is available concerning the possible effects of acetaldehyde on human colonic epithelial cells, this study was aimed to assess whether this compound, either alone or in combination with ethanol, affects such properties of human neoplastic colonocytes that are considered relevant with regard to cancer development. Human colon adenocarcinoma cell line Caco-2 was used as a model of transformed colonocytes, and effects of acetaldehyde and/or ethanol on the proliferation and differentiation of these cells as well as on their adhesion to collagens I and IV, the most important extracellular matrix proteins in the colon, were studied. The results of this study show that acetaldehyde markedly affects the phenotype of Caco-2 cells without having direct cytotoxic effects. Like many carcinogens, it was found to have a dual effect on cell proliferation rate, acute exposure being inhibitory and chronic exposure stimulating. Acetaldehyde also considerably decreased both sucrase activity and nuclear content of protein kinase A catalytic subunit in Caco-2 cells, which indicate that the differentiation of the cells was disturbed. Moreover, the adhesion of Caco-2 cells to collagens I and IV was dose-dependently reduced by acetaldehyde treatment. All these changes, i.e. enhanced cell proliferation rate (by chronic treatment), decreased differentiation, and reduced adhesion to extracellular matrix proteins, would in vivo predict more aggressive and invasive tumour behaviour. The possibility that colonic intraluminal acetaldehyde, either ethanol-derived or endogenous, might enhance the development of colorectal tumours should therefore be considered.

Acetaldehyde↗