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PubMed1997

A comprehensive model for enrofloxacin to ciprofloxacin transformation and disposition in dog.

The pharmacokinetics of enrofloxacin and ciprofloxacin, its major active metabolite, were determined in dog after oral and intravenous administrations of enrofloxacin and intravenous infusion of ciprofloxacin. A comprehensive model of enrofloxacin and ciprofloxacin disposition was constructed to investigate the extent of enrofloxacin to ciprofloxacin transformation and the influence of the hepatic first-pass effect on the parent compound oral bioavailability. Plasma levels were measured using a validated HPLC method. Enrofloxacin and ciprofloxacin plasma concentration data were fitted simultaneously using a set of differential equations describing a six-compartment model (two compartments for each analyte, one for the liver, and one for the intestinal tract); it was assumed that only a fraction of enrofloxacin was metabolized to ciprofloxacin and that this conversion only occurred in the liver. The fitted parameters obtained from the model were used to calculate plasma clearances (0.729 +/- 0.212 L/h/kg for enrofloxacin, 0.468 +/- 0.094 L/h/kg for ciprofloxacin), distribution volumes (2.45 +/- 0.49 L/kg for enrofloxacin, 1.92 +/- 0.33 L/kg for ciprofloxacin), mean residence times (3.47 +/- 0.78 h for enrofloxacin, 4.20 +/- 0.82 h for ciprofloxacin), and the fractions of enrofloxacin metabolized to ciprofloxacin after intravenous and oral administrations of enrofloxacin. It was shown that enrofloxacin was largely metabolized to ciprofloxacin and that the fractions of metabolized enrofloxacin were similar after intravenous and oral administrations of enrofloxacin (40.44 +/- 10.08 and 40.17 +/- 8.33%, respectively), the hepatic first-pass effect being low (7.15 +/- 1.99%).

Administration, Oral↗
PubMed2005

A probabilistic model of face mapping with local transformations and its application to person recognition.

This paper proposes a new measure of "distance" between faces. This measure involves the estimation of the set of possible transformations between face images of the same person. The global transformation, which is assumed to be too complex for direct modeling, is approximated by a patchwork of local transformations, under a constraint imposing consistency between neighboring local transformations. The proposed system of local transformations and neighboring constraints is embedded within the probabilistic framework of a two-dimensional hidden Markov model. More specifically, we model two types of intraclass variabilities involving variations in facial expressions and illumination, respectively. The performance of the resulting method is assessed on a large data set consisting of four face databases. In particular, it is shown to outperform a leading approach to face recognition, namely, the Bayesian intra/extrapersonal classifier.

Algorithms↗
PubMed1993

The dimensionality of texture-defined motion: a single channel theory.

We examine apparent motion carried by textural properties. The texture stimuli consist of a sequence of grating patches of various spatial frequencies and amplitudes. Phases are randomized between frames to insure that first-order motion mechanisms directly applied to stimulus luminance are not systematically engaged. We use ambiguous apparent motion displays in which a heterogeneous motion path defined by alternating patches of texture s (standard) and texture v (variable) competes with a homogeneous motion path defined solely by patches of texture s. Our results support a one-dimensional (single-channel) model of motion-from-texture in which motion strength is computed from a single spatial transformation of the stimulus--an activity transformation. The value assigned to a point in space-time by this activity transformation is directly proportional to the modulation amplitude of the local texture and inversely proportional to local spatial frequency (within the range of spatial frequencies examined). The activity transformation is modeled as the rectified output of a low-pass spatial filter applied to stimulus contrast. Our data further suggest that the strength of texture-defined motion between a patch of texture s and a patch of texture v is proportional to the product of the activities of s and v. A strongly counterintuitive prediction of this model borne out in our data is that motion between patches of different texture can be stronger than motion between patches of similar texture (e.g. motion between patches of a low contrast, low frequency texture 1 and patches of high contrast, high frequency texture h can be stronger than motion between patches of similar texture h).

Contrast Sensitivity↗
PubMed2026

Sequence optimization targeting mRNA stability enhances monoclonal antibody titers in CHO cells.

This study presents a DNA sequence optimization approach that integrates mRNA stability as a tunable design parameter to enhance monoclonal antibody expression in Chinese hamster ovary (CHO) cells. A comprehensive combinatorial library of synonymous coding-sequence variants of an IgG1 light chain was integrated as single copies at a defined genomic locus in CHO cells with identical regulatory elements. Steady-state mRNA abundance, quantified by deep sequencing of gDNA and mRNA, served as a proxy for mRNA stability. These data were used to train a machine learning model that predicts mRNA abundance from coding sequence using embeddings from a pre-trained nucleotide transformer. This abundance predictor, together with established translational metrics, was incorporated into a genetic algorithm for multi-objective codon optimization. As proof-of-concept, we optimized sequences encoding Trastuzumab to either maximize or minimize the abundance criterion and obtained benchmark sequences from two commercial providers. Using targeted integration, we generated CHO cell lines and measured protein titer and cell-specific productivity. Sequences optimized for high abundance significantly increased intracellular mRNA levels (+41%), protein titer (+59%), and cell-specific productivity (+85%) relative to low-abundance designs, while viable cell densities remained comparable. Compared to commercial benchmarks, high-abundance sequences achieved significantly higher titer (+70%) and cell-specific productivity (+98%). These findings establish mRNA stability as a practical and complementary design parameter for codon optimization in monoclonal antibody production, with potential applicability to other proteins and expression systems.

CHO↗
PubMed1999

Relationship between metallothioneins and metals in a natural population of the clam Ruditapes decussatus from Sfax coast: a non-linear model using Box-Cox transformation.

Cadmium, copper and zinc were determined concomitantly with metallothionein-like proteins (MTLPs) in the subcellular fractions of Ruditapes decussatus digestive gland. This study covered 4 months and aimed to evaluate the effect of metal pollution and other factors such as sex, size and reproductive state on MTLP levels. Copper concentrations did not vary with month, however Cd and Zn concentrations showed high levels during August. Organisms showing low cadmium concentrations presented the highest cadmium percentages in the soluble fraction (SF) containing MTLPs. However for high cadmium concentrations, the insoluble fraction (IF) was implicated in cadmium association. MTLP levels varied according to the month, the sex and the size of the organisms. A non-linear model based on the Box-Cox transformation, was proposed to describe a positive and a significant relationship between MTLPs and the studied metals. A model including sex and size showed that these two factors affected MTLP levels, but were less important than metals. Males of R. decussatus showed higher significant correlations between MTLP levels and cadmium than females. Moreover, the effect of size and reproductive state on MTLP levels was less perceptible in males than in females. As a result, MTLPs in males of R. decussatus could be proposed as suitable biomarker for detecting metal contamination.

Animals↗
PubMed1981

Control of energy transformation of mitochondria. Analysis by a quantitative model.

A mathematical model of control of energy transformation in mitochondria is presented. The considered processes are: the proton translocation by the respiratory chain, the production of ATP by ATPase, the translocation of adenine nucleotides and of phosphate by their translocators, and a passive backflow of protons through the mitochondrial membrane. The mathematical equations expressing the steady-state kinetics of these processes and the relations between them were derived on the basis of current experimental data. The model predicts fairly well the values of the proton electrochemical gradient, of the ATP/ADP ratios within and outside mitochondria and of the distribution of phosphate between both compartments in different metabolic states of mitochondria. From the general agreement of model computations with experimental data, it is suggested that the electron flux through the respiratory chain is immediately controlled by the energy back-pressure of the proton electrochemical gradient, that the ATPase reaction is near equilibrium in phosphorylating mitochondria but that the adenine nucleotide exchange across the mitochondrial membrane requires some loss of energy. The latter is caused by an inhibition of the translocator by ATP from the outer side or by ADP from the inner side depending on the actual ATP/ADP in both compartments. It explains that no fixed relation exists between the rate of respiration and the phosphorylation state of extramitochondrial adenine nucleotides. The relation is modified by the concentration of phosphate and by intramitochondrial energy utilization.

Adenine Nucleotides↗
PubMed1997

A proposed density-dependent model of long slender to short stumpy transformation in the African trypanosomes.

A simple arithmetic model is developed that is based upon the assumption: (1) that transformation of replicating long slender Trypanosoma brucei to nonreplicating short stumpy forms is parasite population density dependent; (2) that as the slender population increases there is a change in the external environment that triggers the slender to stumpy transformation; and (3) that stumpy forms of T. brucei do not induce the change in external environment that triggers slender to stumpy transformation or do so to a lesser extent than slender forms, thus preventing the proportion of stumpy forms in a population from reaching 100%. A simulation based on these assumptions shared many features with curves on numbers of long slender, intermediate, and short-stumpy forms of T. brucei during the first parasitemic wave of the 3 T. brucei subspecies in intact and immunosuppressed inbred mice.

Animals↗
PubMedDate not supplied

Modelling health-related performance indices.

PRIMARY OBJECTIVE: The purpose of the present review is to critically examine the various models used to describe health-related performance indices (e.g. grip-strength, lung function, arterial blood pressure, anaerobic and aerobic power, etc.). MAIN OUTCOMES AND RESULTS: The majority of health-related performance indices are known to increase proportionally with body size and decline with age, although some, for example arterial blood pressure and cholesterol, increase with both age and excessive body weight. Historically, the confounding effects of body size and age have been controlled using multiple linear or polynomial regression models assuming a constant additive error variance. Based on maximum likelihood goodness-of-fit criterion, an alternative class of allometric models with a multiplicative error term arc shown to describe such proportional relationships more adequately in both cross-sectional and longitudinal studies. CONCLUSIONS: When modelling health-related performance indices, multiplicative, allometric models incorporate the concept of a proportional association as an integral part of its model form. Such models guarantee realistic values of health-related response variables both within and beyond the range of observations, ensuring biologically sound estimates of the response variables for subjects of all ages. After a logarithmic transformation, the models can be fitted using ordinary linear regression that will naturally help to overcome the heteroscedasticity observed in such data. However, if the logarithmic transformation fails to provide a constant error variance, an alternative approach is to model the error variance itself using log-linear regression. For longitudinal data, the use of multilevel modelling provides an alternative method of modelling error variation observed in health-related performance indices.

Adolescent↗
PubMed1992

Functional imaging and localization of electromagnetic brain activity.

Functional imaging of electric brain activity requires specific models to transform the signals recorded at the surface of the human head into an image. Two categories of model are available: single-time-point and spatio-temporal methods. The instantaneous methods rely only on the few voltage differences measured at one sampling point. To create a spatial image from this limited information, they require strict assumptions that rarely conform with the underlying physiology. Spatio-temporal models create two kinds of images: first, a spatial image of discrete equivalent multiple dipoles or regional sources, and second, an image of source current waveforms that reflect the temporal dynamics of the brain activity in circumscribed areas. The accuracy of the spatial image is model dependent and limited, but it can be validated from the spatio-temporal data by the "regional source imaging" technique, introduced here. The source waveforms are linear combinations of the scalp waveforms, and thus, specific derivations which image local brain activities at a macroscopic level. Brain source imaging of somatosensory evoked potentials revealed temporally overlapping activities from the brainstem, thalamus and from multiple sources in the region of the contralateral somatosensory projection areas.

Brain↗
PubMed2004

Relationships between bone mass and circulating leptin concentrations in Hutterites.

A limited number of previous studies have shown inverse associations between bone mass or density and circulating leptin in humans. Relationships between bone mass and circulating leptin in Hutterites, who have elevated bone density, are unknown. Knowledge gained from studies in mice suggests that Hutterites exhibit traits consistent with a deficiency in circulating leptin or in leptin signaling. We examined relationships between whole body (WB) and regional (lumbar, total hip, femoral neck, trochanter) bone mineral content (BMC) by dual energy X-ray absorptiometry and circulating leptin in 249 Hutterites (137 female) ages 20-55 years and 72 similarly aged non-Hutterites (37 female). We tested the hypothesis that (1) Hutterites will have low circulating leptin concentrations for a given amount of body fat compared to non-Hutterites, and (2) controlling for body fat, there will be an inverse relationship between BMC and circulating leptin among Hutterites. Hutterites had higher BMC than non-Hutterites at all skeletal sites after adjusting for site-specific bone area, age, and sex (P </= 0.02). Hutterite females had higher leptin concentrations than non-Hutterite females [geometric mean and 95% confidence interval (CI): 18.38 (17.18, 19.67) vs. 14.30 (12.55, 16.28), P </= 0.001) after adjusting for WB fat mass. Hutterite males also had higher leptin concentrations than non-Hutterite males [geometric mean and 95% CI: 6.53 (6.11, 6.98) vs. 5.62 (4.98, 6.35), P = 0.03) after adjusting for WB fat mass. We used backward stepwise regression to determine significant (P </= 0.10) covariates to include in models predicting WB and regional BMC among Hutterites (separately by sex). Subsequently, we entered leptin (log-transformed) to models to test for significance (P </= 0.05). After adjusting for covariates, leptin concentration was not a significant predictor of BMC at any site, in either sex, among Hutterites. It is possible that genetic influences that interfere with hypothalamic leptin signaling, in a manner unrelated to adipocyte leptin production, contribute to elevated Hutterite bone density.

Adult↗
PubMed1990

Cellular F-actin levels as a marker for cellular transformation: relationship to cell division and differentiation.

Transformation is associated with profound structural and quantitative changes in the cytoskeleton. Herein we report studies using F-actin, a major cytoskeletal protein, as a quantitative marker for transformation cells, focusing on separating the effects of the cell cycle, cell differentiation, and transformation. The model system for these studies consisted of three lymphoblastic cell lines, one untransformed line (RPMI) and two transformed lines, one (HL-60) of which can be induced to differentiate and the other (Daudi) which cannot. The relation of F-actin levels to cell cycle was studied by flow cytometry with the use of fluorescein-phalloidin to label F-actin and propidium iodide to label DNA. F-actin levels in transformed Daudi and HL-60 lines were only two-thirds that of the untransformed RPMI cells. Histograms of the distribution of F-actin showed that the transformed lines consisted of two cell populations, one having an F-actin content near that of untransformed cells and the other having much less. Cell cycle analysis showed that F-actin in untransformed cells increased 10-15% as cells entered the S compartment, remaining approximately constant through G2 + M phases of the cell cycle, but in transformed cells the major increase in F-actin occurred during G2 + M phase. Double-label studies with rhodamine-phalloidin for F-actin and KI-67 monoclonal antibody for dividing cells (cells at late G1, S, G2, and M) measured with quantitative fluorescence image analysis showed that the mean F-actin content of dividing cells was twice that of nondividing cells. These results suggested that most of the cell division-related F-actin increase occurred during late G1 phase in untransformed cells. Differentiation of HL-60 cells with dimethyl sulfoxide or retinoic acid normalized the F-actin content of the nondividing cell population, but dimethyl sulfoxide and retinoic acid produced no detectable change in F-actin in the undifferentiable Daudi cells. A tumor promoter (12-O-tetradecanoylphorphol-13-acetate) inhibits differentiation of hematopoietic cells, resulted in a 32% decrease in the mean F-actin content of RPMI cells due to the appearance of a new subpopulation of low F-actin content. The 12-O-tetradecanoylphorbol-13-acetate-induced changes reversed slowly after removal of 12-O-tetradecanolyphorbol-13-acetate but more rapidly in the presence of retinoic acid. These results indicate that F-actin quantification can serve as a marker for cellular transformation and provides a tool for studying the mechanisms of cellular differentiation that may lead to a better understanding of the oncogenic process.

Actins↗
PubMed1983

An analysis of the sensitivity of somatic cell hybrids to natural killer cell- and natural cytotoxic cell-mediated lysis.

The analysis of the NK and NC sensitivity of somatic cell hybrids formed between parental cell lines that differ in their NK and NC sensitivity has shown the following. 1) The dominant expression of both NK and NC recognition determinants on target cells; 2) the dominant expression of two post-recognitive NC resistance mechanisms, one requiring protein synthesis and one being protein synthesis independent; and 3) the dominant expression of a post-recognitive NK resistance mechanism, which is protein synthesis independent. The post-recognitive protein synthesis-independent NC resistance mechanism confers no NK resistance and the post-recognitive NK resistance mechanism confers no NC resistance. Whether the post-recognitive protein synthesis-dependent NC resistance mechanism confers NK resistance remains open to question. The analysis of the hybrids indicates that transformed cells become sensitive to either NK- or NC-mediated lysis by losing their resistance to the lytic activity of these effector cells, and it appears that differentiation plays a role in determining whether NK or NC resistance will be lost upon transformation. A model is proposed in which the differentiation into a fibroblast associates the loss of NC resistance with transformation, whereas the differentiation into a lymphocyte associates the loss of NK resistance with transformation. Because the loss of NK resistance is not associated with the transformation of fibroblasts, they remain NK resistant, and because the transformation of lymphocytes is not associated with the loss of NC resistance, they remain NC resistant. This provides the basis for the target specificity exhibited by NK and NC effectors.

Animals↗
PubMed1997

Characterization of the interaction of Ca2+ with hydroxy and non-hydroxy fatty acid species of cerebroside sulfate by Fourier transform infrared spectroscopy and molecular modeling.

Ca2+-mediated interactions between the carbohydrate groups of glycolipids, including that of cerebroside sulfate (galactosylceramide I3-sulfate), have recently been implicated as a basis of cell recognition and adhesion. Hydroxylation of the fatty acid of this lipid has an effect on these interactions. Therefore, FT-IR spectroscopy was used to study the interaction of Ca2+ with semisynthetic hydroxy (HFA) and non-hydroxy fatty acid (NFA) species of cerebroside sulfate (CBS). Ca2+ caused partial dehydration of the sulfate group and reduced hydrogen bonding of the sugar hydroxyls of both species. The amide I and II bands of the lipids in the absence of Ca2+ (NH4+ salt forms) suggested that the N-H of the HFA species is involved in a bent intramolecular hydrogen bond, probably with the fatty acid hydroxyl group and the glycosidic oxygen, while that of the NFA species is involved in a linear intermolecular hydrogen bond with the C=O and/or other oxygens. Ca2+ caused a rearrangement of the hydrogen-bonding network in the interfacial region of the HFA species involving the amide group. The results suggested increased hydrogen bonding of the C=O and a shift in hydrogen bonding of the N-H of the Ca2+ salt form of the HFA species from a bent intramolecular hydrogen bond to a linear intermolecular hydrogen bond, probably with the C=O of neighboring molecules, similar to the NFA species. The involvement of the fatty acid alpha-hydroxyl group in the rearranged network was indicated by a reduction in mobility of the alpha-CH group of the HFA species, in contrast to that of the NFA species. Participation of the alpha-OH group in hydrogen-bonding networks in the interfacial region of both the NH4+ and Ca2+ salt forms caused a significant increase in the interchain packing, as evident from correlation field splitting of the HFA-CBS methylene scissoring mode, while this did not occur for the NFA species. The absence of intramolecular hydrogen bonding of the N-H with the glycosidic oxygen for both salt forms of the NFA species and for the Ca2+ salt form of the HFA species may destabilize the "bent shovel", bilayer planar conformation of the sugar and cause it to be in the extended, bilayer perpendicular conformation. Calculations of the three-dimensional interaction energy of Ca2+ with CBS showed strong binding around the sulfate and the surface of galactose facing the bilayer in the bent shovel conformation. Ca2+ binding at this surface would disrupt intra- and intermolecular hydrogen-bonding interactions of the head group, thus accounting for its effect in inducing a transition to the extended conformation.

Binding Sites↗
PubMed2002

Reshaping medical volumetric data for enhanced visualization.

Three dimensional volume datasets are now commonly produced in the medical sciences. These datasets are generated by observational equipment such as CT, MRI, and ultrasound. There is a significant amount of research in techniques to render these datasets quickly and more realistically. However, there is little or no work on intuitive methods to manipulate volume datasets and volume models. For example, one may want to view a colon stretched out or unraveled. While techniques exist to transform polygonal models, similar techniques are not available for volumetric data. In this work, we describe our methodology to "reshape volumes" and remap existing volumetric datasets using volumetric skeletons. We demonstrate our results by unraveling a 3D colon dataset and discuss the many potential uses of this new visualization methodology.

Anatomy, Cross-Sectional↗
PubMed2006

Compartmental modeling of the fluorescence anisotropy decay of a cylindrically symmetric brownian rotor: Identifiability analysis.

We present the results of the deterministic identifiability analysis based on similarity transformation for models of one-state excited-state events of cylindrically symmetric rotors in isotropic environments undergoing rotational diffusion described by Brownian reorientation. Such an analysis on error-free time-resolved fluorescence (anisotropy) data can reveal whether the parameters of the considered model can be determined. The fluorescence delta-response functions I(parallel)(t) and I(perpendicular)(t), for fluorescence polarized respectively parallel and perpendicular to the electric vector of linearly polarized excitation, are used to construct, in convenient matrix form, expressions of the sum S(t) = I(parallel)(t) + 2I(perpendicular)(t), the difference D(t) = I(parallel)(t) - I(perpendicular)(t), and the time-resolved fluorescence anisotropy r(t) = D(t)/S(t). The identifiability analysis of r(t) demonstrates that the rotational diffusion coefficients D(parallel) and D(perpendicular) for rotation respectively about and perpendicular to the symmetry axis can be uniquely resolved. However, the polar and azimuthal angles defining the absorption and emission transition moments in the molecular reference frame are not individually identifiable. Nevertheless, the difference between the polar angles of these transition moments is uniquely determined.

Journal Article↗
PubMed1988

Spirometry in healthy adult never-smokers.

Spirometry was performed in 277 female and 240 male subjects constituting a random, unbiased population sample representative for the population of Denmark. Equipment, calibration and measurement procedures conformed strictly with established standards. Statistical analysis showed that certain power transformations (cubic, quadratic or square root) of the data produced models that fitted the data statistically significantly better than linear models, where no transformations are applied, or logarithmic models where a logarithmic transformation is applied to the response variable. Differences between predictions obtained with the three models were, however, small and without practical significance. Neither rigid adherence to established, well documented standards nor elaborate statistical analysis reduced the inter-individual variance significantly in comparison to previous investigations. The results emphasize that it is important that reference values are appropriate for the methods and populations in question.

Adult↗
PubMed2006

Fractional Fourier transform for partially coherent off-axis Gaussian Schell-model beam.

The fractional Fourier transform (FRT) is applied to a partially coherent off-axis Gaussian Schell-model (GSM) beam, and an analytical formula is derived for the FRT of a partially coherent off-axis GSM beam. The corresponding tensor ABCD law for performing the FRT of a partially coherent off-axis GSM beam is also obtained. As an application example, the FRT of a partially coherent linear laser array that is expanded as a sum of off-axis GSM beams is studied. The derived formulas are used to provide numerical examples. The formulas provide a convenient way to analyze and calculate the FRT of a partially coherent off-axis GSM beam.

Journal Article↗