Biomedical subjects

N Julen

Publications and source records attributed to N Julen.

14 recordsLinked to original sources

PubMed2003

Computational integrative physiology: at the convergence of the life and computational sciences.

OBJECTIVE: In this paper we outline how Computational Integrative Physiology (CIP) can help unravel the mechanisms of normal and pathological biological processes. Our objective is to illustrate how CIP is firmly grounded on the life and computational sciences. METHOD: After describing a general theoretical frame-work for CIP, we will center our discussion on cardiac rhythmic disorders with a particular focus on the Long QT syndrome that will serve as a case example. Within this context, we will describe multi-scale processes in biological, medical and in general mathematical terms, starting from the control of gene expression to the electrical activity of the entire heart. We will therefore proceed from the smaller microscopic scales to the larger macroscopic ones. In doing so, we will illustrate, at least in a qualitative sense, how CIP can be accomplished by showing some of the relations that can exist between mathematical variables characterizing models of different space-scales. CONCLUSION: We will conclude by putting forth how CIP and the related fields of bioinformatics and medical informatics are necessary to derive meaningful knowledge from the huge and exponentially growing biological and medical data.

Biological Science Disciplines↗

PubMed1998

An interactive 3D anisotropic cellular automata model of the heart.

A 3D cellular anisotropic automata model with modifiable geometry is described. The modeling parameters include grain size, fiber orientation, and free-wall and septal thickness. From this modifiable model, three specific models corresponding to normal heart, left ventricular hypertrophy, and ventricular dilatation were generated. Each model is a conduction and propagation model in which the atria, the major atrial vessel bases, the ventricles, and the specialized conduction system are represented. Muscle tissues are modeled as bundles of fibers with anisotropic conduction speed of the activation wavefronts. Regional variations of conduction, refractory gradients, and regional potential gradients can also be specified before each simulation. Each element has adaptive properties with respect to cycle length and to the prematurity of incoming impulses. Action potentials can be specified for each cell and an equivalent source formulation is carried out to simulate the vectorcardiogram and the corresponding 12-standard-lead electrocardiogram.

Arrhythmias, Cardiac↗

PubMed1998

A qualitative model for computer-assisted instruction in cardiology.

CARDIOLAB is an interactive computational framework dedicated to teaching and computer-aided diagnosis in cardiology. The framework embodies models that simulate the heart's electrical activity. They constitute the core of a Computer-Assisted Instruction (CAI) program intended to teach, in a multimedia environment, the concepts underlying rhythmic disorders and cardiac diseases. The framework includes a qualitative model (QM) which is described in this paper. During simulation using QM, dynamic sequences representing impulse formation and conduction processes are produced along with the corresponding qualitative descriptions. The corresponding electrocardiogram (ECG) and ladder diagram are also produced, and thus, both qualitative notions and quantitative facts can be taught via the model. We discuss how qualitative models in particular, and computational models in general can enhance the teaching capability of CAI programs.

Cardiology↗

PubMed1997

Spatio-temporal reasoning for multi-scale modeling in cardiology.

In this paper, we present an overview of the CARDIOLAB environment where the heart's electrical activity is modeled at distinct space and time scales. CARDIOLAB uses three models, two of which are based on cellular automata, and the third on qualitative simulation. They are combined around a blackboard for multi-scale quantitative and qualitative modeling of cardiac electrical activity. A general account on how spatio-temporal representation and reasoning methods are applied to produce heuristic associations is also presented.

Computer Simulation↗

PubMed1995

Reduced CD21 (CR2) and CD54 (ICAM-1) expression in MT2 cells with HIV-1 or HIV-2 strains.

Alterations in the expression of cell-surface receptors have been reported in HIV-infected cells for CD4, CD25 (IL-2 receptor), CD2, CD3 and CD8 and CD26. In the present study we provide evidence that CD21 is down-regulated in the human T-lymphoblastoid cell line MT2 after infection with HIV-1 and -2 isolates. The same effect was observed with ICAM-1 (CD54). CD21 expression was monitored by means of fluorescence intensity, its functional ability to bind to C3d and by quantitative measurement of CD21-antigen in supernatants and cell lysates using an immunoassay. In addition, the decrease of CD21 and ICAM-1-specific mRNA suggests a mechanism at a transcriptional level. Our data suggest that HIV might have a direct influence on the receptor expression.

Cell Line, Transformed↗

PubMed1994

A novel, complement factor H-related regulatory protein expressed on the surface of human B cell lines.

Complement regulatory proteins present on the surface of various mammalian cells play an important role in controlling homologous lysis, by interacting with C3 (and usually C4). These proteins have a similar structural motif ("short consensus repeat") (Reid, K.B.M., Bentley, R.D., Campbell, R.D., Chung, L.P., Sim, R.B., Kristensen, T. and Tack, B.F., Immunol. Today 1986. 7:230), and the genes encoding them are members of the family of regulators of complement activation. Here we describe a hitherto unknown member of this family, a molecule expressed by B lymphoblastoid cells. This protein is recognized by polyclonal antibodies to factor H and by MAH4, a monoclonal antibody reacting with the N-terminal portion of factor H. The cell surface protein is built up of two disulfide-linked chains of approximately 68 and 75 kDa. Biosynthetic labeling studies confirmed that it is synthesized by B cells only, but not by the investigated lines of other origin. When tested for its functional activity, this molecule was shown to act as cofactor for factor I-mediated cleavage of fluid-phase C3b to C3bi. The protein appears to be encoded by a 3.5-kb mRNA, hybridizing with a cDNA probe coding for the N-terminal portion of factor H. Due to its cross-reactivity with anti-H antibodies, cofactor activity for factor I and hybridization with factor H cDNA, despite its two-chain composition, it is considered a factor H-like protein.

B-Lymphocytes↗

PubMed1992

Expression of complement components of the alternative pathway by glioma cell lines.

Glioma cell lines express proteins of the complement alternative pathway, namely C3, factor B, factor H, and factor I. Secretion of these proteins was shown by a sensitive and specific ELISA. C3 and factor H were rapidly secreted by glioma cell line CB193 and reached a concentration of 140 ng/ml/10(6) cells after 72 h of culture. Factor B and factor I were secreted at a lower rate and reached concentrations of 25 and 15 ng/ml/10(6) cells, respectively. Western blot and immunoprecipitation experiments showed that secreted proteins were identical to the corresponding plasma proteins. For factor H, besides the well known 150-kDa species, an additional polypeptide of 45 kDa with factor H immunoreactivity was observed. This species corresponded to the N-terminal truncated form found in plasma. In preliminary experiments, we observed control of these syntheses by cytokines. IL-1 beta significantly increased C3 secretion, with no effect on factor H. Secretion of factor H was enhanced by IFN-gamma. These results show that a glioma cell line could be a useful tool to study complement biosynthesis by glial cells in humans.

Complement C3↗

PubMed1992

In vitro biosynthesis of complement factor I by human endothelial cells.

We have studied the secretion of the complement regulatory protein factor I by human umbilical vein endothelial cells (HUVEC). Northern and Western blot analysis and biosynthetic labeling experiments indicate that HUVEC secrete factor I at very low levels in basal conditions and that this secretion is significantly enhanced by interferon-gamma. Analysis of the proteolytic inactivation of C3b by HUVEC supernatants show that factor I is secreted in a functional form and can promote the specific proteolytic inactivation of C3b to iC3b. Together with previous studies establishing the secretion of complement factor H by HUVEC, this work demonstrates that the endothelial cell is able to secrete in its environment two complement regulatory proteins, factor I and factor H, which can mediate the degradation of C3b to iC3b. The secretion of factor I by HUVEC provides a useful in vitro model to analyze the modulation of this secretion and may be relevant to the local deposition of iC3b at the surface of the endothelium during the inflammatory reaction.

Cells, Cultured↗

PubMed1992

Differential modulation by glucocorticoids of alternative complement protein secretion in cells of the monocyte/macrophage lineage.

The effect of the synthetic glucocorticoid dexamethasone (DXM) on the secretion by human monocytes of alternative complement proteins C3, factor B and factor H was investigated. Results indicated that DXM modulates this secretion in a direction which would be consistent with its anti-inflammatory properties. DXM, at therapeutic concentrations, had a suppressive effect on C3 and factor B secretion and a stimulatory effect on factor H secretion by monocytes. This differential modulation on C3, factor B and factor H secretion was similar in mature macrophages. Together with previous studies showing that DXM had a suppressive effect on C3 and factor B secretion and a stimulatory effect on factor H secretion by human endothelial cells, our results indicate that DXM appears to have the general property of regulating local production of complement components so as to control complement activation.

Cell Differentiation↗

PubMed1990

Partial hepatectomy and mediators of inflammation decrease the expression of liver alpha 2-HS glycoprotein gene in rats.

Liver mRNA levels of two acute phase reactant (APR) proteins, alpha 2-HS glycoprotein (a major negative APR) and alpha 1-acid glycoprotein (a major positive APR) were measured in male rats at different times after the administration of turpentine, of tumor necrosis factor, or following partial hepatectomy. In every case, a marked decrease in mRNA levels of alpha 2-HS glycoprotein was observed which reached a maximum at 24 h. A concomitant increase of alpha 1-acid glycoprotein mRNA levels was observed under the same conditions. These results indicate that the decreased levels of alpha 2-HS glycoprotein induced by the acute-phase response following inflammatory mediators and partial hepatectomy are due to a down-regulation of the gene expression of this protein in rat liver.

Animals↗

PubMed1990

Expression of complement alternative pathway proteins by endothelial cells. Differential regulation by interleukin 1 and glucocorticoids.

We have studied the secretion of proteins of the alternative pathway of complement C3, factor B and factor H by human umbilical vein endothelial cells (HUVEC). Results showed that factor H and factor B are quantitatively secreted in abundance whereas C3 could only be detected when the cells are maintained in culture during long periods of time. Interferon-gamma stimulated factor H, factor B and, to a lesser extent, C3 secretions. Interleukin (IL) 1 had a differential effect on spontaneous C3, factor B and factor H secretions. In the presence of IL 1, there was a significant secretion of C3 occurring within a short period of culture. IL 1 also stimulated factor B secretion. There was a synergistic stimulating effect between IL 1 and interferon-gamma to bring C3 and factor B productions by HUVEC to very high levels. In contrast, factor H secretion was consistently inhibited by IL 1. Local increase in C3 and factor B secretions by endothelial cells in the presence of IL 1 may have important implications in the inflammatory reaction. In striking contrast, the glucocorticoid dexamethasone (DXM) had modulatory effects which are consistent with its anti-inflammatory properties. DXM, at therapeutic concentrations, decreased C3 and factor B secretions and increased factor H secretion. Local modulation of complement protein secretion by DXM appears to be a new mechanism by which this glucocorticoid may control inflammation.

Complement C3b Inactivator Proteins↗

PubMed1990

[Study of the complement system. General principles and perspectives].

Measurement of complement in clinical medicine is traditionally based on the determination of CH50 and immunochemical and/or functional measurement of complement proteins C1q, factor B, C3 and C4. The interpretation of these measurements, as far as complement activation is concerned, can however be difficult as these tests do not allow to discriminate between consumption due to activation, hereditary deficiency, increased rate of synthesis or even hyposynthesis. This explains why their use as markers of evolutivity in diseases where complement activation is occurring has given variable results. New tests for complement activation have been more recently introduced. These are mainly the measurements of the anaphytotoxins, the degradation products of C3 and the membrane attack complex. As these tests reflect more directly complement activation, they may be more reliable markers. The immunochemical and functional measurements of C1-inhibitor are of special interest as they are the tests which allow definitive diagnosis of the hereditary angio-oedema. General principles for the interpretation of the different tests used to evaluate the complement system are presented and discussed.

Anaphylatoxins↗

PubMed1988

The synthesis of human alpha-2-HS glycoprotein is down-regulated by cytokines in hepatoma HepG2 cells.

The regulation of the synthesis of alpha-2-HS glycoprotein (AHSG) by inflammatory mediators from activated monocytes was studied on the human hepatoma cell line HepG2 and compared to that of albumin. Monocyte-conditioned medium, recombinant human interleukin-6 (rhIL6) and interleukin-1 beta (rhIL1 beta) all down-regulated the synthesis of AHSG. This decrease was found both at the protein and the mRNA level. The most efficient mediator was the monocyte-conditioned medium, when rhIL1 beta was found to be less efficient than rhIL6. The combination of rhIL6 and rhIL1 beta resulted in an additive down-regulation of the AHSG mRNA levels. Similar results were obtained with albumin. These data indicate that AHSG is a negative acute-phase protein whose synthesis is regulated by cytokines in a manner similar to that of albumin.

Blood Proteins↗

PubMedDate not supplied

Differential modulation of complement factor H and C3 expression by TNF-alpha in the rat. In vitro and in vivo studies.

The biosynthesis of alternative regulatory complement protein factor H was investigated using both an in vivo rat model and an in vitro rat hepatocyte culture system, and compared to that of C3 component. Subcutaneous injection of a single dose of 20 micrograms of recombinant murine tumor necrosis factor-alpha (rmTNF-alpha) had no effect on factor H liver mRNA levels, while it increased C3 mRNA levels. In correlation with this, serum factor H levels remained unchanged after rmTNF-alpha injection, whereas C3 levels were increased. In contrast in vitro studies showed that rmTNF-alpha had no effect on factor H and C3 expression by rat hepatocytes. Recombinant human interleukin-1 alpha (rhIL-1 alpha) did not alter the expression of factor H, whereas it increased C3 expression, and recombinant human interleukin-6 (rhIL-6) stimulated expression of both proteins. This study shows that TNF-alpha is not directly responsible for the increased levels of factor H observed in vivo during induced inflammation in the rat. Its in vivo effect on C3 secretion might be secondary to the TNF-alpha-induced release of IL-1 and/or IL-6.

Animals↗