Aberrations of the cylindrical mirror time-of-flight mass spectrometers with oblique incidence.
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Journal Article↗
Biomedical subjects
I Albert
Publications and source records attributed to I Albert.
Investigation of specific substitutions in virulence genes characterizing phenotypic groups of low-virulence field strains of Listeria monocytogenes.
Several models have shown that virulence varies from one strain of Listeria monocytogenes to another, but little is known about the cause of low virulence. Twenty-six field L. monocytogenes strains were shown to be of low virulence in a plaque-forming assay and in a subcutaneous inoculation test in mice. Using the results of cell infection assays and phospholipase activities, the low-virulence strains were assigned to one of four groups by cluster analysis and then virulence-related genes were sequenced. Group I included 11 strains that did not enter cells and had no phospholipase activity. These strains exhibited a mutated PrfA; eight strains had a single amino acid substitution, PrfAK220T, and the other three had a truncated PrfA, PrfADelta174-237. These genetic modifications could explain the low virulence of group I strains, since mutated PrfA proteins were inactive. Group II and III strains entered cells but did not form plaques. Group II strains had low phosphatidylcholine phospholipase C activity, whereas group III strains had low phosphatidylinositol phospholipase C activity. Several substitutions were observed for five out of six group III strains in the plcA gene and for one out of three group II strains in the plcB gene. Group IV strains poorly colonized spleens of mice and were practically indistinguishable from fully virulent strains on the basis of the above-mentioned in vitro criteria. These results demonstrate a relationship between the phenotypic classification and the genotypic modifications for at least group I and III strains and suggest a common evolution of these strains within a group.
Amino Acid Substitution↗
A modified Weibull model for bacterial inactivation.
In this paper, a modified Weibull model is proposed to fit microbial survival curves. This model can incorporate shoulder and/or tailing phenomena if they are encountered. We aim to obtain an accurate fit of the "primary" modelling of the bacterial inactivation and to provide a useful and meaningful model for biologists and food industry. A delta parameter close to the classical concept of the D value, established for sterilisation processes, is used in the model. The specific parameterisation of the Weibull model is evaluated for the parameter of interest delta. The goodness-of-fit of the model is compared to the one produced by the model proposed by Geeraerd et al., [Geeraerd, A.H., Herremans, C.H., Van Impe, J.F., 2000. Structural model requirements to describe microbial inactivation during a mild heat treatment. Int. J. Food Microbiol. 59, 185-209.] on experimental data. As our model provides good fits for the different types of survival curves analysed, further research can focus on the development of suitable secondary model types. In this respect, it is interesting to note that the delta parameter is close to the D concept.
Bacillus↗
HyBrow: a prototype system for computer-aided hypothesis evaluation.
MOTIVATION: Experimental design, hypothesis-testing and model-building in the current data-rich environment require the biologists' to collect, evaluate and integrate large amounts of information of many disparate kinds. Developing a unified framework for the representation and conceptual integration of biological data and processes is a major challenge in bioinformatics because of the variety of available data and the different levels of detail at which biological processes can be considered. RESULTS: We have developed the HyBrow (Hypothesis Browser) system as a prototype bioinformatics tool for designing hypotheses and evaluating them for consistency with existing knowledge. HyBrow consists of a modeling framework with the ability to accommodate diverse biological information sources, an event-based ontology for representing biological processes at different levels of detail, a database to query information in the ontology and programs to perform hypothesis design and evaluation. We demonstrate the HyBrow prototype using the galactose gene network in Saccharomyces cerevisiae as our test system, and evaluate alternative hypotheses for consistency with stored information. AVAILABILITY: www.hybrow.org
Computational Biology↗
Design of a high-sensitivity negative ion source time-of-flight mass analyzer assembly created by cylindrical electrodes with a common axis.
The new design incorporates the negative ion source and the mass analyzer, both constructed from cylindrical electrodes. The ion source is formed by three gridded cylindrical electrodes: a pulsed grid, the intermediate grid and the final accelerating grid. During a first time lapse, the electrons penetrate through the pulsed grid into the retarding field between this grid and the intermediate grid. The electrons are turning at some depth inside this intergrid space, where the attachment to neutral molecules most probably occurs. Next, the pulsed grid becoming strongly negative and ions are extracted towards the final acceleration grid. The ions from the cylindrical surface where they were created concentrate on the common axis of the electrodes (lateral focusing). The source lateral and time focus are coincident. A cylindrical electrostatic mirror is fitted to the source. The design, with a single stage, ensures also lateral focusing of the ions diverging from the common axis of the electrodes. The mirror electric and geometric parameters were selected to ensure both lateral and time focusing on the final detector with subsequent high luminosity. The basic parameters of the specific negative ion source time-of-flight mass analyzer design proposed here, are ion source final acceleration, intermediate, pulsed cylindrical grid radii 10, 20 and 30 mm, respectively, electrostatic mirror earthed grid and ion turning points surface radii 0.6 and 0.8 m, respectively. Ion packet smearing by the ion energy spread (resulting from the initial electron energy spread as electrons are turning at different depths inside the ionization region, from the moment when ions were created, being accelerated towards the pulsed grid during ionization) and by the turnaround time inside the cylindrical field was accounted for. Maintaining very high sensitivity, a resolution of the order of 100 is expected.
Journal Article↗
Determination of indinavir and nelfinavir trough plasma concentration efficacy thresholds according to virological response in HIV-infected patients.
BACKGROUND: There is evidence to suggest a pharmacokinetic-pharmacodynamic relationship in HIV-infected patients receiving protease inhibitor (PI)-containing highly active antiretroviral therapy (HAART); however, the effective trough PI plasma concentrations achieved have not been precisely determined. METHODS: The relationship between HIV viral load and concomitant PI trough plasma concentration (C(trough)) was evaluated in 101 patients receiving at least 4 months of thrice daily indinavir (IDV)-containing (n=68) or nelfinavir (NFV)-containing (n=33) HAART. The more discriminating C(trough) efficacy thresholds were determined statistically for each PI by using the raw C(trough) and the time-corrected C(trough), using the precise delay since the last PI intake and the half-life of each PI. RESULTS: For IDV (P=0.002) and NFV (P=0.019) median C(trough) levels were higher in patients with undetectable viral load [0.23 mg/L (n=30) and 2.3 mg/L (n=16) respectively] than in patients with detectable viral load [0.11 mg/L (n=38) and 0.6 mg/L (n=17) respectively]. C(trough) levels of IDV (r=-0.45; P<0.0001) and NFV (r=-0.43; P=0.011) were correlated with the concomitant viral load. The more discriminating C(trough) efficacy thresholds were estimated statistically as 0.12 mg/L for IDV and 0.5 mg/L for NFV. When C(trough) values were time-corrected, the C(trough) efficacy thresholds, 8 h after the last intake, were 0.15 mg/L for IDV and 0.65 mg/L for NFV. CONCLUSIONS: These results support the importance of achieving minimal effective C(trough) to improve the virological efficacy of PI-containing HAART, and specify the target concentrations for IDV and NFV.
Antiretroviral Therapy, Highly Active↗
Experimental validation of low virulence in field strains of Listeria monocytogenes.
Several reports have described Listeria monocytogenes strains which were nonpathogenic or weakly pathogenic, but little is known about these low-virulence strains. We found that 9 field L. monocytogenes strains were hypovirulent and 17 were avirulent, based on the number of mice contaminated and the colonization of their spleens after subcutaneous inoculation. All these strains possessed the known virulence genes. We have now assessed the low virulence of these strains in other assays before determining how they differ from virulent strains. We have shown that the low-virulence strains exhibited a phenotypic stability and were not a mixture of virulent and avirulent bacteria. They did not recover virulence after many passages in mice and colonized the spleens of mice more poorly than virulent strains after i.v. inoculation. Their lethal capacities, determined by 50% lethal dose (LD(50)), were lower than those of virulent strains. Like Listeria innocua, 14 of 17 avirulent strains had no LD(50) and were eliminated by the lymph nodes after subcutaneous inoculation. The virulent, hypovirulent, and avirulent strains were always significantly different, whatever the tests of virulence used, confirming the importance of these low-virulence field strains in identifying the proteins involved in virulence.
Animals↗
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↗
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↗
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↗
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↗
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↗
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↗
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↗
Precipitating factors of transient global amnesia.
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Amnesia↗
Dynamic technique: three-flap SMAS.
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Dissection↗
[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↗
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↗