PubMed Health⌕ Search

Biomedical subjects

I Albert

Publications and source records attributed to I Albert.

At least 19 recordsLinked to original sources
PubMed2002

Sensitivity analysis for high quantiles of ochratoxin A exposure distribution.

Using available data from a consumption survey and contamination data on ochratoxin A (OA) in food, a sensitivity analysis (SA) for high quantiles (95th and 99th quantiles) of OA exposure distribution was carried out, obtained by a Monte Carlo simulation in French children. Exposure assessment for food contaminants is important to control the risk of foodborne diseases. Risk assessors are interested in high quantiles of contaminant exposure distributions. As these exposure distributions are generally very asymmetrical, it is difficult to obtain relevant and stable high quantiles in such a context. Determining OA exposure distribution is complex because it is based on the sum of elementary exposure distributions (eight foodstuffs are analysed here), and each one of these is the product of a consumption distribution and a contamination distribution. The SA enables us to quantify the influences of the parameter variability of the consumption and contamination probability density functions (pdf) which have been fitted to the data, our simulation model inputs, on the 95th and 99th quantiles of the output exposure distribution. After some preliminary trials, we have postulated a quadratic polynomial regression model for the quantiles of OA exposure distribution in view of undertaking this SA. This regression model comprises 32 main factors, their 496 two-factor interactions and their 32 quadratic terms. The 32 factors are the parameters of the fitted pdf: 16 parameters of Gamma distributions relative to the eight consumed foods and 16 parameters of Gamma distributions relative to the eight food OA contaminations. For an optimal parameter estimation of such a large model, we used an experimental design approach depending on a resolution-V fractional factorial design of 6561 experiments. The factor ranges are established by a preliminary study of bootstrap sampling. From the bootstrap samples, the factor ranges are obtained taking into account the correlation between the two parameters of the fitted Gamma pdf. A full exposure distribution is simulated for each of the 6561 experiments. The consumption dependencies are taken into account by the Iman and Conover method. On the basis of this analysis, validated and useful models for each desired quantile are obtained showing a major influence of the parameters of "Cereals" (consumption and contamination) and slightly less so for parameter of "Pork" consumption in the sensitivity of the quantiles.

Adolescent↗
PubMed2001

Granular drag on a discrete object: shape effects on jamming.

We study the drag force on discrete objects with circular cross section moving slowly through a spherical granular medium. Variations in the geometry of the dragged object change the drag force only by a small fraction relative to shape effects in fluid drag. The drag force depends quadratically on the object's diameter as expected. We do observe, however, a deviation above the expected linear depth dependence, and the magnitude of the deviation is apparently controlled by geometrical factors.

Journal Article↗
PubMed2001

Modeling relaxation and jamming in granular media.

We introduce a stochastic microscopic model to investigate the jamming and reorganization of grains induced by an object moving through a granular medium. The model reproduces the experimentally observed periodic sawtooth fluctuations in the jamming force and predicts the period and the power spectrum in terms of the controllable physical parameters. It also predicts that the avalanche sizes, defined as the number of displaced grains during a single advance of the object, follow a power law P(s) approximately s(-tau), where the exponent is independent of the physical parameters.

Journal Article↗
PubMed2001

Stick-slip fluctuations in granular drag.

We study fluctuations in the drag force experienced by an object moving through a granular medium. The successive formation and collapse of jammed states give a stick-slip nature to the fluctuations which are periodic at small depths but become "stepped" at large depths, a transition that we interpret as a consequence of the long-range nature of the force chains and the finite size of our experiment. Another important finding is that the mean force and the fluctuations appear to be independent of the properties of the contact surface between the grains and the dragged object. These results imply that the drag force originates in the bulk properties of the granular sample.

Journal Article↗
PubMed2000

Jamming and fluctuations in granular drag

We investigate the dynamic evolution of jamming in granular media through fluctuations in the granular drag force. The successive collapse and formation of jammed states give a stick-slip nature to the fluctuations which is independent of the contact surface between the grains and the dragged object, thus implying that the stress-induced collapse is nucleated in the bulk of the granular sample. We also find that while the fluctuations are periodic at small depths, they become "stepped" at large depths, a transition which we interpret as a consequence of the long-range nature of the force chains.

Journal Article↗
PubMed2000

The use of frailty models in genetic studies: application to the relationship between end-stage renal failure and mutation type in Alport syndrome. European Community Alport Syndrome Concerted Action Group (ECASCA).

BACKGROUND: Alport syndrome (AS) is a severe hereditary disease usually transmitted as an X dominant trait and involving a mutation of the COL4A5 gene. It leads to end-stage renal failure (ESRF), but this progression is heterogeneous. Mutations of the COL4A5 gene have been characterised in numerous families using molecular biology. Our objective was to evaluate the interfamilial heterogeneity of the disease and to study relationships between mutation types and progression to ESRF in the European Community Alport Syndrome Concerted Action group (ECASCA) registry database. METHODS: We used the frailty model framework. Frailty models have been developed to analyse censored data with non-independent observations. Random effects are introduced in a Cox proportional regression model to take into account the intracluster correlations. In this study, ESRF is considered a censored event and the intrafamilial correlations are taken into account in the frailty models. RESULTS: These approaches allow us to demonstrate the existence of an interfamilial heterogeneity; the role of the mutation type explains the interfamilial variability. In particular, the results suggest that some mutation types are associated with a higher risk of ESRF for males. CONCLUSIONS: This study shows the importance of characterising the mutation at the molecular level in genetic studies, to understand the relationship between genotype and phenotype. The frailty models constitute an attractive approach in this context, when the phenotype is characterised by a censored end-point.

Alleles↗
PubMed1999

The F-box protein beta-TrCP associates with phosphorylated beta-catenin and regulates its activity in the cell.

Defects in beta-catenin regulation contribute to the neoplastic transformation of mammalian cells. Dysregulation of beta-catenin can result from missense mutations that affect critical sites of phosphorylation by glycogen synthase kinase 3beta (GSK3beta). Given that phosphorylation can regulate targeted degradation of beta-catenin by the proteasome, beta-catenin might interact with an E3 ubiquitin ligase complex containing an F-box protein, as is the case for certain cell cycle regulators. Accordingly, disruption of the Drosophila F-box protein Slimb upregulates the beta-catenin homolog Armadillo. We reasoned that the human homologs of Slimb - beta-TrCP and its isoform beta-TrCP2 (KIAA0696) - might interact with beta-catenin. We found that the binding of beta-TrCP to beta-catenin was direct and dependent upon the WD40 repeat sequences in beta-TrCP and on phosphorylation of the GSK3beta sites in beta-catenin. Endogenous beta-catenin and beta-TrCP could be coimmunoprecipitated from mammalian cells. Overexpression of wild-type beta-TrCP in mammalian cells promoted the downregulation of beta-catenin, whereas overexpression of a dominant-negative deletion mutant upregulated beta-catenin protein levels and activated signaling dependent on the transcription factor Tcf. In contrast, beta-TrCP2 did not associate with beta-catenin. We conclude that beta-TrCP is a component of an E3 ubiquitin ligase that is responsible for the targeted degradation of phosphorylated beta-catenin.

Animals↗
PubMed1999

[Methodology for analyzing censored correlated data: application of marginal and frailty approaches in human genetics. The European Community Alport Syndrome Concerted Action Group (ECASCA)].

BACKGROUND: Statistical analysis for correlated censored data allows to study censored events in clustered structure designs. Considering a possible correlation among failure times of the same group, standard methodology is no longer applicable. We investigated proposed models in this context to study familial data about a genetic disease, Alport syndrome. Alport syndrome is a severe hereditary disease due to abnormal collagenous chains. Renal failure is the main symptom of the disease. It progresses toward end-stage renal failure (IRT) according to a high time variability. As shown by genetic studies, mutations of COL4A5 gene are involved in the X-linked Alport Syndrome. Due to the large range of the mutation types, the aim of this study was to search for a possible genetic origin of the heterogeneity of the disease severity. METHODS: Marginal survival models and mixed effects survival models (so-called frailty models) were proposed to take into account the possible non independence of the observations. In this study, time until end-stage renal failure is a rightly censored end point. Possible intra-familial correlations due to shared environmental and/or genetic factors could induce dependence among familial failure times. In this paper, we fit marginal and frailty proportional hazards models to evaluate the effect of mutation type on the risk of IRT and an interfamilial heterogeneity of failure times. RESULTS: In this study, the use of these models allows to show the presence of an interfamilial heterogeneity of the failure times to IRT. Moreover, the results suggest that some mutation types are linked to a higher risk of fast evolution to IRT, which explains partially the interfamilial heterogeneity of the failure times. CONCLUSIONS: This paper shows the interest of marginal and frailty models to evaluate the heterogeneity of censored responses and to study relationships between a censored criterion and covariables. This study puts forward the importance of characterizing the mutation at a molecular level to understand the relationship between genotype and phenotype.

Data Interpretation, Statistical↗
PubMed1998

Gibbs sampler for the logistic model in the analysis of longitudinal binary data.

Logistic mixed-effects models constitute a natural framework to study longitudinal binary response variables when the question addressed with the data is related to covariate effects within persons. However, the computations of the likelihoods are generally tedious and require the resolution of integrals which have no analytical solution. In this paper, we study a logistic mixed-effects model in a Bayesian framework and use the Gibbs sampler to overcome the current computational limitations. From a study of side-effects occurring during plasma exchanges, we explore the issues of bayesian formulation, model parametrization, choice of the prior distributions, diagnosing convergence, comparison between models and model adequacy. Finally, we show that a Bayesian random-effects model is useful to facilitate prediction.

Bayes Theorem↗
PubMed1998

The 18 kDa cytochrome c553 from Heliobacterium gestii: gene sequence and characterization of the mature protein.

The 18 kDa cytochrome c553 is the dominant c-type cytochrome in cell membranes of Heliobacterium gestii. After solubilization, this cytochrome was purified in three steps as a complex with two other proteins of 32 and 42 kDa. The redox midpoint potential of the cytochrome c553 was determined to be +215 mV. The EPR spectra clearly show the presence of an ascorbate-reducible low-spin heme with gz = 3.048 and gy = 2.238. The gx = trough could not be detected. In addition, a Cu(II) signal with g = 2.058 was observed, indicating that one component of the cytochrome c553 complex contains a bound copper ion. The gene for the 18 kDa cytochrome c553, cyhA, consists of 429 bp coding for a protein of 142 amino acids. The association of the cytochrome with the cytoplasmic membrane is mediated by two fatty acid molecules, one palmitate and one stearate, that could be identified by mass spectrometry. Both fatty acids are most likely bound to the cysteine residue of the N-terminally processed protein via a glycerol moiety. The amino acid sequence deduced from the DNA sequence exhibits partial identity to the membrane-bound cytochrome c551 from Bacillus PS3 [Fujiwara, Y., Oka, M., Hamamoto, T., and Sone, N. (1993) Biochem. Biophys. Res. Commun. 1144, 213-219] and to the cytochrome c subunit (NorC) of the nitrous reductase from Pseudomonas stutzeri [Zumft, W. G., Braun, C., and Cuypers, H. (1994) Eur. J. Biochem. 219, 481-490].

Amino Acid Sequence↗
PubMed1997

Induction of a beta-catenin-LEF-1 complex by wnt-1 and transforming mutants of beta-catenin.

Signal transduction by beta-catenin involves its posttranslational stabilization and import to the nucleus where it interacts with transcription factors. Recent implications for beta-catenin signaling in cancer prompted us to examine colon cancer cell lines for the expression of LEF-1, a transcription factor that binds to beta-catenin. The analysis of several cell lines revealed the expression of LEF1 mRNA and a constitutive association of the LEF-1 protein with beta-catenin. In contrast to the colon cells, PC12 and 293 cells did not contain a beta-catenin-LEF-1 complex, even though both proteins were detected in cell lysates. In these cells, the association of endogenous LEF1 and beta-catenin was induced by stimulation with the wnt-1 proto-oncogene. The complex formed following transient stimulation with wnt-1 and also persisted in cells stably expressing wnt-1. Ectopic overexpression of beta-catenin in 293 cells also induced the assembly of the beta-catenin-LEF-1 complex and activated gene transcription from a LEF-1-dependent promotor. Expression of mutant oncogenic forms of beta-catenin identified in cancer cells resulted in higher levels of transcriptional activity. The results suggest that a cancer pathway driven by wnt-1, or mutant forms of beta-catenin, may involve the formation of a persistent transcriptionally active complex of beta-catenin and LEF1.

Animals↗
PubMed1997

Loss of beta-catenin regulation by the APC tumor suppressor protein correlates with loss of structure due to common somatic mutations of the gene.

The mutation cluster region in the APC gene defines a region of approximately 660 bp, in which the vast majority of its somatic mutations are found. These mutations disrupt the polypeptide chain, typically eliminating five of the seven repeated sequences of 20 amino acids (aa) each in the central region of the APC protein. To examine the relationship between loss of this structure and loss of function, we constructed APC deletion mutants that progressively truncated the protein across the mutation cluster region. The mutants were tested for their association with beta-catenin and their ability to down-regulate it in SW480 cells. The binding of beta-catenin to APC fragments required the inclusion of only a single 20-aa repeat sequence, whereas down-regulation required the presence of at least three of these repeat sequences, and those including the second repeat exhibited the highest activity. The mutation of three conserved serine residues in the second repeat greatly reduced the activity of an otherwise highly active APC fragment. Thus, the repeated 20-aa sequence is directly implicated in beta-catenin turnover. The elimination of at least five of these seven repeats due to somatic mutations suggests that loss of beta-catenin regulation by APC is selected for during tumor progression.

Adenomatous Polyposis Coli Protein↗
PubMed1997

Stabilization of beta-catenin by genetic defects in melanoma cell lines.

Signal transduction by beta-catenin involves its posttranslational stabilization and downstream coupling to the Lef and Tcf transcription factors. Abnormally high amounts of beta-catenin were detected in 7 of 26 human melanoma cell lines. Unusual messenger RNA splicing and missense mutations in the beta-catenin gene (CTNNB1) that result in stabilization of the protein were identified in six of the lines, and the adenomatous polyposis coli tumor suppressor protein (APC) was altered or missing in two others. In the APC-deficient cells, ectopic expression of wild-type APC eliminated the excess beta-catenin. Cells with stabilized beta-catenin contained a constitutive beta-catenin-Lef-1 complex. Thus, genetic defects that result in up-regulation of beta-catenin may play a role in melanoma progression.

Adenomatous Polyposis Coli Protein↗
PubMed1997

The effects of the alpha 2 adrenoceptor blocker idazoxan on defeat-induced immobility and plasma corticosterone in rats is antagonized by administration of adrenocorticotrophin-antiserum.

Adult male Wistar rats were introduced into the home cage of residents accustomed to aggressive encounters. The attacks of the residents induced lasting immobility in the subjects. The alpha-2 adrenoceptor blocker idazoxan (which elicits an increase in brain norepinephrine release probably by the blockade of presynaptic autoreceptors) induced an enhancement of defeat-induced corticosterone secretion as well as a reduction in immobility. Pre-treatment with adrenocorticotrophin (ACTH) antiserum abolished both the increased adrenomedullar stress reaction and the reduction in immobility. It is concluded that norepinephrine-induced corticosterone secretion is involved in the immobility-lowering effects of alpha-2 adrenoceptor blockers. In previous experiments we have shown that the norepinephrine-induced increase in the aggressiveness of the residents depends on the ability to secrete corticosterone. Therefore it appears that the effects of norepinephrine on social conflict are at least partly mediated by corticosterone. This implies the involvement of acute corticosterone changes in fight/flight behaviours.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed1996

Binding of GSK3beta to the APC-beta-catenin complex and regulation of complex assembly.

The adenomatous polyposis coli gene (APC) is mutated in most colon cancers. The APC protein binds to the cellular adhesion molecule beta-catenin, which is a mammalian homolog of ARMADILLO, a component of the WINGLESS signaling pathway in Drosophila development. Here it is shown that when beta-catenin is present in excess, APC binds to another component of the WINGLESS pathway, glycogen synthase kinase 3beta (GSK3beta), a mammalian homolog of Drosophila ZESTE WHITE 3. APC was a good substrate for GSK3 beta in vitro, and the phosphorylation sites were mapped to the central region of APC. Binding of beta-catenin to this region was dependent on phosphorylation by GSK3 beta.

Adenomatous Polyposis Coli Protein↗
PubMed1996

Deletion of an amino-terminal sequence beta-catenin in vivo and promotes hyperphosporylation of the adenomatous polyposis coli tumor suppressor protein.

Regulation of cell adhesion and cell signaling by beta-catenin occurs through a mechanism likely involving the targeted degradation of the protein. Deletional analysis was used to generate a beta-catenin refractory to rapid turnover and to examine its effects on complexes containing either cadherin or the adenomatous polyposis coli (APC) protein. The results show that amino-terminal deletion of beta-catenin results in a protein with increased stability that acts in a dominant fashion with respect to wild-type beta-catenin. Constitutive expression in AtT20 cells of a beta-catenin lacking 89 N-terminal amino acids (deltaN89beta-catenin) resulted in severely reduced levels of the more labile wild-type beta-catenin. The mutant beta-catenin was expressed at endogenous levels but displaced the vast majority of wild-type beta-catenin associated with N-cadherin. The deltaN89beta-catenin accumulated on the APC protein to a level 10-fold over that of wild-type beta-catenin and recruited a kinase into the APC complex. The kinase was highly active toward APC in vitro and promoted a sodium dodecyl sulfate gel band shift that was also evident for endogenous APC from cells expressing the mutant beta-catenin. Unlike wild-type beta-catenin, which partitions solely as part of a high-molecular-weight complex, the deltaN89 mutant protein also fractionated as a stable monomer, indicating that it had escaped the requirement to associate with other proteins. That similar N-terminal mutants of beta-catenin have been implicated in cellular transformation suggests that their abnormal association with APC may, in part, be responsible for this phenotype.

Adenomatous Polyposis Coli Protein↗