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PubMed1992

Statistical properties of the NOAEL.

The use of the no observed adverse effect level (NOAEL) in setting allowable exposure levels for noncancer endpoints is a source of controversy. Based on computer simulations and empirical studies, several authors have criticized the use of the NOAEL in terms of its sensitivity to sample size and its high sampling variability from experiment to experiment. The purpose of this paper is to derive the statistical distribution of the NOAEL. Using Weibull models, we investigate the impact of the shape of the underlying dose-response curve on the distribution of the NOAEL. The results confirm previous criticisms of the NOAEL and show that average risk levels associated with the NOAEL may be substantial. These results provide additional motivation for developing alternative approaches to risk assessment.

Animals↗

PubMed1983

Nonspecific binding of lac repressor to DNA. II. A small-angle neutron-scattering study.

Complexes between lac repressor and DNA fragments from mononucleosomes have been studied by small-angle neutron scattering. Both the radius of gyration and the molecular weight of the complexes were measured, and the experimental results were interpreted according to a model with two types of complex (M. Charlier and J.-C. Maurizot, Biophys. Chem. 18 (1983) 303), and a statistical distribution of repressor on the DNA fragments. Good agreement between the model calculations and the experimental results was obtained. We concluded that there was an absence of strong cooperativity and of network formation between the complexes. The second type of binding, which does not induce any spectroscopic change, is marked by an increase in molecular weight of the complexes. Kinetic measurements were also made, which allowed the determination of the lifetime of the nonspecific DNA-repressor complexes.

DNA↗

PubMed1992

Selective laser spectroscopy of 1-phenylnaphthylamine in phospholipid membranes.

Time-resolved and steady-state spectra and kinetics of anisotropy of 1-phenylnaphthylamine (1-AN) fluorescent probe in phosphatidylcholine bilayer membranes have been examined using a nanosecond laser spectrofluorimeter. In this system we consider two kinds of inhomogeneous broadening of spectra, the first of which is due to different probe locations in membrane, while the second one is due to the statistical distribution of interaction energy within a given location. This broadening causes the red shift of the fluorescence spectrum at red-edge excitation, the specific dependences of instantaneous fluorescence and fluorescence anisotropy spectra on the wavelength of excitation. A field diagram is presented which, by describing the free energy levels of the polar fluorescent probe in membranes, makes it possible to unambiguously interpret the whole set of experimental data. It is suggested that the release of potential energy of intermolecular interactions which occurs in the process of relaxation, results in accelerated (light-induced) rotation of the probe inside the membrane.

1-Naphthylamine↗

PubMed1991

On the handedness of the scaffolds of sister chromatids.

We discuss a mechanical model for the mirror-symmetric inversion of the scaffold's helicity of replicated chromatids vis-a-vis that of their templates. The paper ends with comments on the orientability of certain genes and on the effects of such topologies upon (a)symmetric gene expression, in general. Our model and its generalizations apply only to the special subclass of 'coiled' chromatids whose statistical distribution in the genome of normal and of malignant cells is not known precisely.

Biomechanical Phenomena↗

PubMed1986

Intercapillary distance measurement as an indicator of hypoxia in carcinoma of the cervix uteri.

The mean tumor intercapillary distance (ICD) was measured in 44 patients in Stages IIB and III carcinoma of the cervix uteri using a histo-chemical procedure for staining capillary endothelial cells. A mean ICD of 304 +/- 30 microns was obtained, which was independent of the clinical stage and histological grade of differentiation. For each tumor, the proportion of ICD's greater than an arbitrarily chosen value of 300 microns (approximately twice the maximum oxygen diffusion range) was calculated using the normal frequency distribution statistics. The mean ICD and this proportion decreased progressively during the course of external beam pelvic irradiation up to a dose of 4000 cGy. The mean ICD was greater in patients who suffered local recurrence within two years than in patients whose tumors remained controlled. This applied to pre-treatment values and measurements performed after the delivery of 2000 and 4000 cGy. The proportion of ICD's greater than 300 microns showed a similar trend. No significant correlation was found between the hemoglobin concentration at time of presentation and either the mean ICD, or the probability of local control. It is proposed that ICD measurement may be a useful tool to identify subgroups of tumors where hypoxia can interfere with the effectiveness of radiotherapy.

Capillaries↗

PubMed1985

Complete nucleotide sequence of the hexokinase PI gene (HXK1) of Saccharomyces cerevisiae.

The nucleotide sequence of the yeast glycolytic hexokinase isoenzyme PI-gene, HXK1, has been determined by sequencing the yeast DNA insert of the previously isolated plasmid HXK1 clone [Entian et al., Mol. Gen. Genet. 198 (1984) 50-54]. The structural gene sequence included 1452 bp coding for 484 amino acid (aa) residues corresponding to the Mr of 153 605 for the HXK1 monomer. Several initiation regions and termination points were located using nuclease S1 mapping. The HXK1 sequence was 76% homologous with that of HXK2, which is responsible for triggering glucose repression in yeasts. Since HXK1 is not involved in this regulatory system, the regulatory function of HXK2 must correspond to one or more of the differences between both isoenzymes. Most changes in the amino acid sequence were statistically distributed; however, four clustered regions with more than five altered aa residues were identified.

Amino Acid Sequence↗

PubMed1988

Multiple coronary angioplasty: a model to discriminate systemic and procedural factors related to restenosis.

To assess the interrelation of clinical and procedural factors responsible for restenosis, 119 patients undergoing coronary arteriography were studied a mean of 5.8 +/- 3 months after successful multiple percutaneous transluminal coronary angioplasty. In all clinical, angiographic and procedural variables, the 119 patients undergoing repeat catheterization were similar to the 87 patients that did not. Overall, restenosis occurred in 74 (34%) of 215 lesions. Sixty-three patients had no restenosis, 44 had at least one restenosis and 12 had restenosis at all angioplasty sites. The statistical distribution of restenoses did not follow a binomial model, suggesting that restenosis is more than a lesion-specific phenomenon. Of all the clinical and procedural variables assessed by multivariate logistic regression analysis, only percent stenosis before angioplasty (p less than 0.01), diabetes mellitus (p less than 0.01) and percent stenosis after angioplasty (p less than 0.05) were predictive of restenosis in the entire group. Patients with no restenosis and patients with restenosis at all sites were not different with respect to procedural variables; however, patients with restenosis at all sites more often (p less than 0.05) had diabetes and recent onset angina. In contrast, patients with no restenosis differed from patients with isolated restenosis with respect to procedural variables: severity of stenosis before and after angioplasty, balloon/artery lumen ratio and maximal inflation pressure. Thus, procedural factors may be more related to isolated restenosis, but patient-related factors such as diabetes and recent onset angina may play a more important role in patients with multiple restenoses.

Aged↗

PubMed1986

Effect of activity on the selective stabilization of the motor innervation of fast muscle posterior latissimus dorsi from chick embryo.

The role of neuromuscular activity in the maturation of the motor innervation was investigated in the fast focally innervated posterior latissimus dorsi (PLD) muscle of the chick embryo. The axonal supply in the PLD motor nerve, and the focal multiple innervation of the endplates were described on days 15 and 16 of embryonic life in normal and experimental embryos. In the first series of experiments, chick embryos were paralyzed by repeated injections between days 4 and 10 in ovo of the curare-like agent, flaxedil. Twice more axons in the PLD motor nerve and about twice more nerve terminal profiles at the endplates in the PLD muscles were found in paralyzed than in control embryos. In a second series of experiments, electrodes were implanted around the spinal cord of 7-day-old embryos and electric pulses delivered at 0.5 Hz frequency from day 10 to days 15-16 of incubation. At day 15.5, no change was observed in the axonal supply in the PLD motor nerve of stimulated embryos, while a two-fold decrease was observed in the number of motor nerve terminal profiles per endplate in the corresponding PLD muscle. The statistical distribution of the number of motor nerve terminal profiles per endplate was described from complete semi-serial sections in the PLD muscle from normal, paralyzed and stimulated chick embryos. In these three cases, the distribution of supernumerary nerve terminal profiles followed a Poisson law after one nerve ending had been subtracted from the number of nerve endings counted per endplate.

Animals↗

PubMed1993

Effects of collateral inhibition in a model of the immature rat cerebellar cortex: multineuron correlations.

A model of the immature rat cerebellar cortex is used to simulate the effect of the inhibitory recurrent collateral axons of the Purkinje cells on the spike trains in the network. Inhibition induces an important overall change in the statistical characteristics of individual spike trains. It is also instrumental in producing a strong cooperativity between the different neurons. Moreover, a functional spatial anisotropy appears. A specific entropy index is used to analyze levels of information transfer between clustered and faraway neurons in the network. The formatting effect of recurrent collateral inhibition on spike trains and on network functional dynamics is studied by means of a model of the newborn rat cerebellar cortex. This immature structure has simpler morphological characteristics and fewer physiological parameters than the adult one. It is thus a good candidate for the comparison between experimental and theoretical data. The model network is made of 256 formal neurons (FN), arranged in a square lattice. Each neuron is coupled to its eight nearest neighbors by inhibitory links. All the parameters of the different elements of the model--in particular integration of inhibitory and excitatory inputs--are given anatomical and physiological values derived from biological data. Activities of single FNs and correlations between spatially distant ones are analyzed with classical statistical techniques as well as with a specific informational entropy method we introduce. Simulation results indicate that inhibition is instrumental in: (1) the transformation of the spike train characteristics. This includes a lengthening of the mean interspike interval as well as an overall change in the statistical distribution of intervals, with an emergence of long-lasting ones; (2) the functional structuration of the network. Inhibitory connections between nearest neighbors induce a strong cooperativity between FNs. Furthermore a clear spatial anisotropy occurs in the functioning of the network, with inhibitory effects extending beyond local connectivity in preferential directions. We propose an interpretation of this functional structuration in terms of the various routes followed by the inhibition, including relay effects. The parameters of the model (levels of activities, inhibition rules and connectivities) were varied in order to test the robustness of the above results. Finally, the results are compared with those obtained in an experimental situation.

Animals↗

PubMed2004

Synthesis, characterization and antiviral activity against influenza virus of a series of novel manganese-substituted rare earth borotungstates heteropolyoxometalates.

A series of novel manganese-substituted mixed-valence rare earth borotungsto-heteropoly blues, Ln2H3[BW9(VI)W2(V)Mn(H2O)O39] x 12H2O (Ln(2), Ln = La, Ce, Pr, Nd, Sm, Eu and Gd), as well as their corresponding heteropoly acids (Ln(0)), have been prepared and characterized by cyclic voltammetry (CV), infrared (IR), ultraviolet (UV), thermal gravimetric (TG) and differential thermal (DTA) analysis, X-ray photoelectron spectroscopy (XPS) and electrochemistry. It's shown that the heteropoly blues anion in Ln(2) still retains the alpha-Keggin structure but with a slight distortion as heteropoly acids do, and Mn and W atoms distribute statistically in the whole molecular. At the same time, the cell toxicity and antiviral activity of these rare earth borotungstateheteropoly blues against influenza virus type A and type B in MDCK cells have been investigated using plaque reduction assay. The results elucidated that these complexes exhibit a significantly inhibitory activity and almost no cytotoxicity comparable with those obtained from virazole, and the anti-virus activity depend on the structure of these complexes.

Animals↗

PubMed2005

Influence of homologous disaccharides on the hydrogen-bond network of water: complementary Raman scattering experiments and molecular dynamics simulations.

A comparative investigation of trehalose, sucrose, and maltose in water solution has been performed using Raman scattering experiments and Molecular Dynamics simulations. From the analysis of the O-H stretching region in the [2500,4000] cm(-1) Raman spectral range, which includes for the first time the contribution of 'free' water, and the statistical distribution of water HB probabilities from MD simulations, this study confirms the privileged interaction of trehalose with water above a peculiar threshold weight concentration of about 30%. The role of the hydration number of sugars--found higher for trehalose--on the destructuring effect of the water hydrogen bond network is also addressed. The analysis of the water O-H-O bending spectral range [1500,1800] cm(-1) reveals a change of the homogeneity of water molecules influenced by sugars, but the three investigated sugars are found to behave similarly.

Computer Simulation↗

PubMed2004

Quantitative analysis of collagen fiber angle in the submucosa of small intestine.

It is of interest to know how distension changes the angle and content of collagen in the submucosa of small intestine. We describe the application of a two-dimensional quantitative analysis technology to determine the angles between collagen fibers in the submucosa using digital image processing. A polarization microscope was used to obtain a series of animal intestinal slice images. The images were studied by analyzing the relationship between the pixel values of each of the polarized angles to obtain the collagen fiber angle. The statistical distribution of the angle as function of the degree of distension can be analyzed.

Animals↗

PubMed2006

Occurrence of phthalate esters in the environment of The Netherlands.

Overviews of levels of n-dibutylphthalate (DBP) and di(2-ethylhexyl)phthalate (DEHP) found in freshwater, marine water, sediment, and fish in the Netherlands are given. Sampling spanned a 9-month period (all seasons except winter) and allowed assessing whether phthalate levels are season dependent. Results obtained are compared to data reported for other Western European countries and a fugacity-based modeling approach is used to assess whether there is equilibrium among the various compartments. Highest levels of dissolved DBP and DEHP were found in freshwater samples, whereas these compounds were usually below the limit of detection (LOD) in marine water and sediment. Median levels were log-normally distributed; statistical analysis showed that sampling season is not a relevant determinant parameter. Similar results were obtained for the freshwater sediment compartment, with DEHP levels exceeding concentrations of DBP. DBP levels in fish were often below the LOD. Nevertheless, mean values around 1.8 microg kg(-1) wet fish were found for both DEHP and DBP. Fugacity calculations revealed that especially for DEHP there is no equilibrium among the compartments. DEHP emissions are directed to water, whereas the calculations reveal that sediments provide a sink for DEHP and there is net transport to air. Although it has been suggested that water is the primary compartment for DBP, fugacity plots suggest that air is the compartment to which emissions are directed dominantly. The data reported are in line with values found in Western Europe.

Animals↗

PubMed2005

The molecular changes during placental detachment.

OBJECTIVES: RCAS1 is a membrane protein that plays a role in the maintenance of maternal immune tolerance during pregnancy. The work presented here demonstrates the results of RCAS1 expression in placenta in cases of placental abruption and patients with retained placental tissue during the third stage of labor. STUDY DESIGN: The placenta tissue samples were obtained during vaginal and cesarean delivery (derived from 117 pregnancies). Pregnant women were divided into four groups according to the onset of labor and the time of placental detachment in term labors. The samples were analyzed by the Western blot method. Statistical analysis was performed using the Shapiro-Wilk procedure. The Mann-Whitney test and Student's t-test were applied to compare the differences between parametric data. RESULTS: The average relative amount of RCAS1 observed in those patients with retained placental tissue was statistically significantly higher than in the patients with placental abruption. CONCLUSION: The differences observed in placental RCAS1 levels confirm the participation of this protein in the inhibition of maternal immune response during gestation. The present results also indicate that RCAS1 participates in the changes in the maternal immune system that take place during parturition and reinforce its potential involvement in the mechanism of placental abruption.

Abruptio Placentae↗

PubMed2005

In silico identification of the key components and steps in IFN-gamma induced JAK-STAT signaling pathway.

Systems biology efforts are increasingly adopting quantitative, mechanistic modeling to study cellular signal transduction pathways and other networks. However, it is uncertain whether the particular set of kinetic parameter values of the model closely approximates the corresponding biological system. We propose that the parameters be assigned statistical distributions that reflect the degree of uncertainty for a comprehensive simulation analysis. From this analysis, we globally identify the key components and steps in signal transduction networks at a systems level. We investigated a recent mathematical model of interferon gamma induced Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling pathway by applying multi-parametric sensitivity analysis that is based on simultaneous variation of the parameter values. We find that suppressor of cytokine signaling-1, nuclear phosphatases, cytoplasmic STAT1, and the corresponding reaction steps are sensitive perturbation points of this pathway.

Computational Biology↗

PubMed2003

Rearrangements and chromosomal evolution.

Comparisons of the genome sequences of related species suggests varying patterns of chromosomal rearrangements in different evolutionary lineages. In this review, I focus on the quantitative characterization of rearrangement processes and discuss specific inventories that have been compiled to date. Of particular interest are the statistical distribution of the lengths of inverted or locally transposed chromosome fragments (notably very short ones), inhomogeneities in susceptibility to evolutionary breakpoints in chromosomal regions, the relative importance of genome doubling in the history of multicellular eukaryotes, and of lateral transfer versus gene gain and loss in prokaryotes. These developments provide challenges to computational biologists to refine, revise and scale up mathematical models and algorithms for analyzing genome rearrangements.

Animals↗

PubMed2005

Relationship between angiographic late loss and target lesion revascularization after coronary stent implantation: analysis from the TAXUS-IV trial.

OBJECTIVES: We sought to evaluate the relationship between angiographic late loss and clinical outcomes in the drug-eluting stent era. BACKGROUND: The interrelationship between angiographic late loss, binary restenosis, and clinical recurrence (target lesion revascularization [TLR]) after coronary stent implantation has been incompletely evaluated. METHODS: Using the angiographic substudy of the TAXUS-IV trial, in which 1,314 patients with de novo coronary lesions were randomized to either the paclitaxel-eluting TAXUS stent or to its bare-metal equivalent, we defined the relationship between in-stent and analysis segment late loss, the shape of the late loss histogram (variance and skewedness), and nine-month TLR. RESULTS: Late loss by several measures was closely related to TLR (area under the receiver-operator curve >0.90). For individual vessels of the size in this study (2.8 +/- 0.5 mm), the likelihood of TLR did not exceed 5% until analysis segment late loss was >0.5 mm, and did not exceed 10% until late loss was >0.65 mm. At greater late losses, the late loss TLR relationship was steep and nearly linear. For the overall patient cohort, the rate of TLR was related, however, not only to median late loss, but also to measures of its statistical distribution (TLR increased with lack of homogeneous biologic response [greater variance and greater right skewedness]). Similar relationships held for late loss measured within the confines of the stent itself. CONCLUSIONS: Coronary stents result in large lumens with "room" to accommodate up to approximately 0.5 to 0.65 mm of tissue (angiographic analysis segment late loss) before the likelihood of clinical restenosis (TLR) exceeds 5% to 10%. These data have important implications toward understanding the absolute and relative efficacy of drug-eluting stents.

Angina Pectoris↗

PubMed2006

Prediction of the micro-fluid dynamic environment imposed to three-dimensional engineered cell systems in bioreactors.

Bioreactors allowing culture medium perfusion overcome diffusion limitations associated with static culturing and provide flow-mediated mechanical stimuli. The hydrodynamic stress imposed to cells will depend not only on the culture medium flow rate, but also on the scaffold three-dimensional (3D) micro-architecture. We developed a CFD model of the flow of culture medium through a 3D scaffold of homogeneous geometry, with the aim of predicting the shear stress acting on cells as a function of parameters that can be controlled during the scaffold fabrication process, such as the scaffold porosity and the pore size, and during the cell culture, such as the medium flow rate and the diameter of the perfused scaffold section. We built three groups of models corresponding to three pore sizes: 50, 100 and 150 microm. Each group was made of four models corresponding to 59%, 65%, 77%, and 89% porosity. A commercial finite-element code was used to set up and solve the problem and to analyze the results. The mode value of shear stress varied between 2 and 5 mPa, and was obtained for a circular scaffold of 15.5 mm diameter, perfused by a flow rate of 0.5 ml/min. The simulations showed that the pore size is a variable strongly influencing the predicted shear stress level, whereas the porosity is a variable strongly affecting the statistical distribution of the shear stresses, but not their magnitude. Our results provide a basis for the completion of more exhaustive quantitative studies to further assess the relationship between perfusion, at known micro-fluid dynamic conditions, and tissue growth in vitro.

Bioreactors↗