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At least 1,099 records · Page 61Linked to original sources
PubMed1999

Ultraviolet radiation mutagenesis of hedgehog pathway genes in basal cell carcinomas.

The identification of mutations in Hedgehog (HH) pathway genes in some basal cell carcinomas (BCC) and the detection of HH pathway dysregulation in almost all BCC confirms the importance of this developmental regulatory pathway in human BCC tumorigenesis. Moreover, the occurrence of UVB signature mutations in key HH pathway genes in BCC provides the first genetic evidence that UV radiation (UVR) may be the principal mutagen involved in BCC tumorigenesis. We review herein current advances in the understanding of the role of the HH pathway in BCC tumorigenesis including transgenic and knock-out animal models of HH pathway dysregulation. Furthermore, we summarize abnormalities in other tumor suppressors and oncogenes including ras and p53 and evidence for interactions between these regulatory genes and the HH pathway.

Animals↗
PubMed1997

Involvement of both the classical and alternate pathways of complement in an ex vivo model of xenograft rejection.

BACKGROUND: It is now generally accepted that complement activation is critical for the hyperacute rejection of xenografts. Activation of the classical pathway as the result of the interaction of xenoreactive IgM xenoantibodies with the vascular endothelium has been observed in all species combinations examined to date. A number of studies using a variety of species combinations have also implicated alternate pathway involvement; however, these studies do not enable a conclusion to be drawn as to whether the alternate pathway can be activated in the complete absence of classical pathway activation. METHODS: In this study, human plasma was depleted of both Clq and factor D and then reconstituted with purified Clq or factor D to restore the classical and alternate complement pathways, respectively. The ability of these modified plasmas to prosecute hyperacute rejection was then examined using an ex vivo isolated mouse heart perfusion model based on the Langendorff system. RESULTS AND CONCLUSIONS: In the mouse to human species combination, both the classical and alternate pathways of complement are independently capable of initiating complement activation and mediating xenograft rejection.

Animals↗
PubMed2004

Gene profiling of in vitro and in vivo models of delayed neutrophil apoptosis: a common pathway?

Mechanisms responsible for the termination of an inflammatory response include the activation of a genetic programme of cellular suicide termed apoptosis, which leads to the elimination of the cellular effectors of acute inflammation, particularly the neutrophil. However, delays in this response result in the persistence of inflammation and the development of inflammatory disorders. Understanding the mechanism that inhibits the process of cell death may be helpful in the treatment of inflammatory disorders. Inflammatory cytokines have been shown to inhibit apoptosis through stabilization of the mitochondria and inhibition of the caspase cascade. To date, how these processes are inhibited remains the central question. We hypothesize that the decision for the delay in neutrophil apoptosis is made through signals delivered on the cell surface, which activate combinations of specific genes that inhibit the cell death pathway. Gene chip microarray experiments were performed in in vivo and in vitro models of delayed neutrophil apoptosis. Analysis has yielded changes in a large number of genes involved in inflammation, metabolism, signalling, mitochondrial function and apoptosis. A number of genes have been identified as suitable targets responsible for the regulation of neutrophil apoptosis and their expression was confirmed by real-time PCR and explored at the level of the protein. Their functional role in the apoptotic response is now being determined. One significant finding is that the gene patterns of delay in vitro and in vivo appear to be different, indicating the possibility for different pathways regulating the delay in neutrophil apoptosis.

Apoptosis↗
PubMed1993

Expression of the complement classical pathway by human glioma in culture. A model for complement expression by nerve cells.

In this paper we demonstrate the synthesis of the components of the classical complement pathway, namely C1q, C1r, C1s, C1-Inh, C2, C4, and C5, by human glioma cell lines (U118MG, T193, and T98G). All these components were structurally, antigenically, and functionally similar to their serum counterparts as determined by biosynthetic labeling experiments, Western blot analysis, and hemolytic assays. Northern blot analysis of mRNA demonstrated that, for each of these components, their specific mRNA had the same size as the equivalent mRNA from hepatic tissue. We could not detect the synthesis of C4bp by these cell lines, and the secretion of C1q was only detected after stimulation by interferon-gamma. All these syntheses were up-regulated by interferon-gamma and tumor necrosis factor. Interleukin-1 beta only increased C2 expression and reproducibly down-regulated C5 secretion when used at high doses. Glioma cell lines appear to be an efficient and convenient model for the analysis of complement expression in human astrocytic cells.

Astrocytes↗
PubMed1994

Diffusion rates and transport pathways of fluorescein isothiocyanate (FITC)-labeled model compounds through buccal epithelium.

The aim of this study was to characterize transport of FITC-labeled dextrans of different molecular weights as model compounds for peptides and proteins through buccal mucosa. The penetration of these dextrans through porcine buccal mucosa (a nonkeratinized epithelium, comparable to human buccal mucosa) was investigated by measuring transbuccal fluxes and by analyzing the distribution of the fluorescent probe in the epithelium, using confocal laser scanning microscopy for visualizing permeation pathways. The results revealed that passage of porcine buccal epithelium by hydrophilic compounds such as the FITC-dextrans is restricted to permeants with a molecular weight lower than 20 kDa. The permeabilities of buccal mucosa for the 4- and 10-kDa FITC-dextran (of the order of 10(-8) cm/sec) were not significantly different from each other or from the much smaller compound FITC. The confocal images of the distribution pattern of FITC-dextrans showed that the paracellular route is the major pathway through buccal epithelium.

Animals↗
PubMed2006

Rotavirus assembly: an alternative model that utilizes an atypical trafficking pathway.

We review here recent advances in our knowledge on trafficking and assembly of rotavirus and rotaviral proteins in intestinal cells. Assembly of rotavirus has been extensively studied in nonpolarized kidney epithelial MA104 cells, where several data indicate that most if not all the steps of rotavirus assembly take place within the endoplasmic reticulum (ER) and that rotavirus is release upon cell lysis. We focus here on data obtained in intestinal cells that argue for another scheme of rotavirus assembly, where the final steps seem to take place outside the ER with an apically polarized release of rotavirus without significant cell lysis. One of the key observations made by different groups is that VP4 and other structural proteins interact substantially with specialized membrane microdomains enriched in cholesterol and sphingolipids termed rafts. In addition, recent data point to the fact that VP4 does not localize within the ER or the Golgi apparatus in infected intestinal cells. The mechanisms by which VP4, a cytosolic protein, may be targeted to the apical membrane in these cells and assembles with the other structural proteins are discussed. The identification of cellular proteins such as Hsp70, flotillin, rab5, PRA1 and cytoskeletal components that interact with VP4 may help to define an atypical polarized trafficking pathway to the apical membrane of intestinal cells that will be raft-dependent and by-pass the classical exocytic route.

Animals↗
PubMed2002

Drosophila melanogaster as a model system for drug discovery and pathway screening.

Although the freakish nightmare world of Mr Samsa may seem completely divorced from our view of the real world, the comparisons between the Drosophila and human genomes indicate that we are a lot closer to insects than we like to think. The use of sophisticated genetic approaches combined with emerging genomics technologies suggest that the fly has much to offer as a tool for understanding basic cellular processes and provides an attractive and complex model system for exploring the molecular basis of human diseases such as cancer, Alzheimer's disease and Huntington's disease.

Animals↗
PubMed1987

Pathways and cycles of runaways: a model for understanding repetitive runaway behavior.

Based on information provided by 149 runaways staying in a Canadian shelter, the authors developed a model that explains repititious running away as the result of youths' cognitive confusion and unrealistic beliefs. The majority of the youths, who had run away an average of 8.9 times, felt that the events that led them to run away were unpredictable, yet 54 percent blamed only themselves for what happened. The paper describes the pathways, cycles, and outcomes of running away; analyzes the relationship between the youths' experiences with prostitution, delinquency, and sexual and physical abuse and the length of time they had been away from home; summarizes the youths' reasons for running away; compares the beliefs of runaways with and without a history of sexual abuse; and discusses interventions.

Adaptation, Psychological↗
PubMed2006

Cdo functions at multiple points in the Sonic Hedgehog pathway, and Cdo-deficient mice accurately model human holoprosencephaly.

Holoprosencephaly (HPE), a common defect of human forebrain development, is associated with haploinsufficiency for genes encoding Sonic Hedgehog (SHH) pathway components. Clinical expression of HPE is extremely variable, but it is rarely associated with defects in other SHH-dependent structures, such as limbs. Here we report that mice lacking the transmembrane protein Cdo, previously implicated in myogenesis, display HPE with strain-specific severity and without limb defects, modeling human HPE and implicating modifier genes as a cause of variability. Shh target gene expression is reduced in the developing forebrains of Cdo-/- mice, and Cdo positively regulates Shh signaling in vitro. Our data suggest that Cdo enhances pathway activity in multiple ways, including at signal reception and via a parallel mechanism required at the level of Gli transcription factors. Specific Cdo domains required for its promyogenic effect are dispensable for its Shh signaling role, suggesting that Cdo has multiple, independent functions.

Animals↗
PubMed1975

A model of NaCl and water flow through paracellular pathways of renal proximal tubules.

To explain how hydrostatic pressure differences between tubule lumen and interstitium modulate isotonic reabsorption rates, we developed a model of NaCl and water flow through paracellular pathways of the proximal tubule. Structural elements of the model are a tight junction membrane, an intercellular channel whose walls transport NaCl actively at a constant rate, and a basement membrane. Equations of change were derived for the channel, boundary conditions were formulated from irreversible thermodynamics, and a pressure-area relationship typical of thin-walled tubing was assumed. The boundary value problem was solved numerically. The principal conclusions are: 1) channel NaCl concentration must remain within a few mOsm of isotonic values for reabsorption rates to be modulated by transtubular pressure differences known to affect this system: 2) basement membrane and channel wall parameters determine reabsorbate tonicity; tight junction parameters affect the sensitivity of reabsorption to transmural pressure; 3) channel NaCl concentration varies inversely with transmural pressure difference; this concentration variation controls NaCl diffusion through the tight junction; 4) modulation of NaCl diffusion through the tight junction controls the rate of isotonic reabsorption; modulation of water flow can increase sensitivity to transmural pressure; 5) no pressure-induced change in permeability of the tight junction or basement membrane is needed for pressure to modulate reabsorption; and 6) system performance is indifferent to the distribution of active transport sites, to the numerical value of the compliance function, and to the relationship between lumen and cell pressures.

Basement Membrane↗
PubMed1995

Tissue factor pathway inhibitor and von Willebrand factor antigen levels in adult respiratory distress syndrome and in a primate model of sepsis.

Tissue factor pathway inhibitor (TFPI) is an anticoagulant protein primarily synthesized by the endothelium. A major fraction (approximately 85%) of TFPI remains associated with the endothelium, whereas a small fraction (approximately 15%) is secreted into the blood. In our attempts to search for a marker(s) of endothelial injury in the setting of adult respiratory distress syndrome (ARDS), we retrospectively measured plasma TFPI levels in patients at risk for and with ARDS caused by several etiologic factors. Plasma von Willebrand factor antigen (vWF-Ag), another endothelial-specific protein, was also measured in these patients. The mean plasma TFPI levels were slightly elevated (approximately 1.3-fold), whereas vWF-Ag levels were significantly elevated (approximately 3-fold) in the at-risk group as compared with those in the normal subjects. Both the TFPI (approximately 1.8-fold) and the vWF-Ag (approximately 4-fold) levels were further elevated in the ARDS group. Moreover, the sequential plasma samples from patients with ARDS had progressively increased levels of vWF-Ag and TFPI up to Days 4 and 8, respectively. Neither plasma vWF-Ag nor TFPI levels correlated with mortality in the at-risk group or the ARDS group. TFPI levels were also measured in bronchoalveolar lavage fluids (BALF). The levels (ng/ml) were: normal subjects, 0.05 +/- 0.02 SE; at-risk group, 0.35 +/- 0.16 SE; ARDS group, 0.99 +/- 0.28 SE. Thus, the BALF TFPI levels were increased approximately 7-fold in the at-risk group and approximately 20-fold in the ARDS group relative to the value in the normal subjects. These findings indicate increased local synthesis of TFPI in the alveolar space both in the at-risk patients and in those with ARDS. In additional studies in a primate model of sepsis, lethal doses (LD100) of E. coli administered to baboons resulted in a progressive increase in TFPI levels (approximately 2-fold at 6 h), whereas sublethal doses caused only minimal increase (approximately 1.2-fold). The vWF-Ag levels were elevated approximately 5-fold after infusion of LD100 concentrations of E. coli at 6 h and 4-fold after infusion of sublethal concentrations of E. coli at 24 h. Autopsies on animals in the LD100 group revealed pulmonary congestion, leukocyte infiltration, edema, and hemorrhage, all suggestive of acute lung injury. Thus, in the setting of acute lung injury plasma vWF-Ag appears to be considerably increased prior to significant damage to the endothelium, whereas increased plasma TFPI occurs only after severe injury.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2003

Metabolic model for glycogen-accumulating organisms in anaerobic/aerobic activated sludge systems.

Glycogen-accumulating organisms (GAO) have the potential to directly compete with polyphosphate-accumulating organisms (PAO) in EBPR systems as both are able to take up VFA anaerobically and grow on the intracellular storage products aerobically. Under anaerobic conditions GAO hydrolyse glycogen to gain energy and reducing equivalents to take up VFA and to synthesise polyhydroxyalkanoate (PHA). In the subsequent aerobic stage, PHA is being oxidised to gain energy for glycogen replenishment (from PHA) and for cell growth. This article describes a complete anaerobic and aerobic model for GAO based on the understanding of their metabolic pathways. The anaerobic model has been developed and reported previously, while the aerobic metabolic model was developed in this study. It is based on the assumption that acetyl-CoA and propionyl-CoA go through the catabolic and anabolic processes independently. Experimental validation shows that the integrated model can predict the anaerobic and aerobic results very well. It was found in this study that at pH 7 the maximum acetate uptake rate of GAO was slower than that reported for PAO in the anaerobic stage. On the other hand, the net biomass production per C-mol acetate added is about 9% higher for GAO than for PAO. This would indicate that PAO and GAO each have certain competitive advantages during different parts of the anaerobic/aerobic process cycle.

Acyl Coenzyme A↗
PubMed1996

Costimulation and autoimmunity.

The past year has seen significant advances in our understanding of the role of the B7-CD28/CTLA-4 pathway in T cell activation and self-tolerance. Recent studies have demonstrated that CTLA-4 is a critical negative regulator of T cell activation and autoreactivity, revealing a previously unsuspected means by which costimulation is involved in the maintenance and breakdown of self-tolerance. Manipulation of this costimulatory pathway in animal models of autoimmunity has shown an important role for this pathway in both the initiation and progression of autoimmune diseases.

Animals↗
PubMed2006

SBML-PET: a Systems Biology Markup Language-based parameter estimation tool.

UNLABELLED: The estimation of model parameters from experimental data remains a bottleneck for a major breakthrough in systems biology. We present a Systems Biology Markup Language (SBML) based Parameter Estimation Tool (SBML-PET). The tool is designed to enable parameter estimation for biological models including signaling pathways, gene regulation networks and metabolic pathways. SBML-PET supports import and export of the models in the SBML format. It can estimate the parameters by fitting a variety of experimental data from different experimental conditions. SBML-PET has a unique feature of supporting event definition in the SMBL model. SBML models can also be simulated in SBML-PET. Stochastic Ranking Evolution Strategy (SRES) is incorporated in SBML-PET for parameter estimation jobs. A classic ODE Solver called ODEPACK is used to solve the Ordinary Differential Equation (ODE) system. AVAILABILITY: http://sysbio.molgen.mpg.de/SBML-PET/. The website also contains detailed documentation for SBML-PET.

Algorithms↗
PubMed2005

Spontaneous polarization in eukaryotic gradient sensing: a mathematical model based on mutual inhibition of frontness and backness pathways.

A key problem of eukaryotic cell motility is the signaling mechanism of chemoattractant gradient sensing. Recent experiments have revealed the molecular correlate of gradient sensing: Frontness molecules, such as PI3P and Rac, localize at the front end of the cell, and backness molecules, such as Rho and myosin II, accumulate at the back of the cell. Importantly, this frontness-backness polarization occurs spontaneously even if the cells are exposed to uniform chemoattractant profiles. The spontaneous polarization suggests that the gradient sensing machinery undergoes a Turing bifurcation. This has led to several classical activator-inhibitor and activator-substrate models which identify the frontness molecules with the activator. Conspicuously absent from these models is any accounting of the backness molecules. This stands in sharp contrast to experiments which show that the backness pathways inhibit the frontness pathways. Here, we formulate a model based on the mutually inhibitory interaction between the frontness and backness pathways. The model builds upon the mutual inhibition model proposed by Bourne and coworkers [Xu et al., 2003. Divergent signals and cytoskeletal assemblies regulate self-organizing polarity in neutrophils. Cell 114, 201-214.]. We show that mutual inhibition alone, without the help of any positive feedback (autocatalysis), can trigger spontaneous polarization of the frontness and backness pathways. The spatial distribution of the frontness and backness molecules in response to inhibition and activation of the frontness and backness pathways are consistent with those observed in experiments. Furthermore, depending on the parameter values, the model yields spatial distributions corresponding to chemoattraction (frontness pathways in-phase with the external gradient) and chemorepulsion (frontness pathways out-of-phase with the external gradient). Analysis of the model suggests a mechanism for the chemorepulsion-to-chemoattraction transition observed in neurons.

Animals↗
PubMed1987

Does galactose feeding provide a valid model of consequences of exaggerated polyol-pathway flux in peripheral nerve in experimental diabetes?

This study was designed to examine the effect of exaggerated polyol-pathway flux on sciatic nerve content of polyols, myo-inositol, and water. Rats with streptozocin-induced diabetes of 3- and 12-wk duration and nondiabetic rats fed for 5 days on a diet containing 20% galactose were employed initially. All three conditions showed marked elevation of nerve polyol content, combined with fructose accumulation in the diabetic rats. Galactose-fed rats showed a significant (P less than .01) increase in nerve water content of approximately 30% (when expressed as water/unit dry wt tissue). Diabetic rats showed no change in nerve water. Both diabetic and galactose-fed rats showed a depletion of nerve free myo-inositol, although the extent of depletion was greater in the latter. All these changes were prevented or attenuated by the aldose reductase inhibitor Statil (ICI 128436). When diabetic rats were fed a 20% galactose diet for 5 days, nerves of 3- but not 12-wk diabetic rats showed marked increases in water content. A more mild degree of galactosemia, induced by 5 or 21 days of feeding a diet containing 10% galactose to nondiabetic rats, provoked an increase in nerve water content associated with polyol levels of a similar order to those seen in diabetes. We do not know why polyol-pathway metabolites cause nerve hyperhydration in galactosemia but not in streptozocin-induced diabetes. Such differences urge caution in the use of galactose feeding to model the consequences of exaggerated polyol-pathway flux in nerve to face questions related to neuronal dysfunction in diabetes.

Animals↗
PubMed2005

Novel fragmentation pathway for CID of (b(n) - 1 + Cat)+ ions from model, metal cationized peptides.

We report a new fragmentation pathway for the CID of (b3 - 1 + Cat)+ product ions derived from the model peptide AXAG, where X = beta-alanine, gamma-aminobutyric acid, epsilon-amino-n-caproic acid, or 4-aminomethylbenzoic acid. By changing the amino acid to the C-terminal side of the amino acid X, and incorporating 15N and 13C labeled residues at the same position, we conclude that the dissociation pathway most likely leads to a metal cationized nitrile. With respect to the various amino acids at position X, the putative nitrile product becomes more prominent, relative to the conventional (a3 - 1 + Cat)+ species, in the order beta-alanine < gamma-aminobutyric acid < epsilon-aminocaproic acid < 4-aminomethylbenzoic acid. The pathway is not observed for peptides with alpha-amino acids at position X. The product ion is observed most prominently during the CID of Li+ and Na+ cationized peptides, only to a small extent for Ag+ cationized peptides, and not at all from protonated analogues.

Cations↗