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PubMed2002

Pharmacokinetic study of infusional valspodar.

The pharmacokinetics of valspodar (PSC 833), a selective second-generation P-glycoprotein modulator, was evaluated as part of a Phase I study to modulate paclitaxel therapy in 15 patients with refractory malignancies. Valspodar was given intravenously at 1.42 mg/kg/h for 2 hours, followed by a 27-hour continuous infusion at 0.42 mg/kg/h. Serial blood samples were obtained after intravenous infusion of valspodar and paclitaxel. Valspodar disposition was best described by a linear two-compartment model. The median (range) valspodar clearance was 0.40 ml/min/kg (0.07-1.40 ml/min/kg). The 20-fold interpatient variability in valspodar clearance was not correlated with age, body weight, orgender but might be associated with coadministered medications that were metabolized via cytochrome P450 3A-mediated elimination. Valspodar whole-blood concentrations were maintained above the target threshold of 1000 ng/ml for a median of 32 hours. The pharmacokinetic model generated from this study allows for application in future studies to optimize the use of valspodar.

Adult↗
PubMed1994

Automated method for characterization of diastolic transmitral Doppler velocity contours: late atrial filling.

We develop an automated method of characterizing the late atrial filling phase of diastole by fitting a kinematic model for diastolic filling to the clinical Doppler A-wave contour. The result is a set of model parameters which completely characterizes the contour. We have previously derived a parameterized diastolic filling (PDF) model, which predicts the time-dependent transmitral blood flow velocity obtained by Doppler echocardiography. An automated method to determine the PDF model parameters for early rapid filling from the clinical Doppler E-wave has also been developed and validated. The method consists of digitizing the acoustic Doppler waveform, recreating the Doppler velocity profile, extracting the maximum velocity envelope, and fitting the PDF model for early filling to the envelope. In the current work, we apply the same general approach for PDF parameter determination for the late atrial filling phase of diastole. To assess the presence and significance of near-degeneracies in the model parameter set, numerical experiments (consisting of fitting the model to a model-generated contour to which Gaussian noise was added) were performed. These revealed a two-dimensional degeneracy in four-dimensional parameter space which could be removed by using two kinematic simplifications: critical damping and resonant forcing. We show that these degeneracy-eliminating approximations do not limit the ability of the model to predict clinical A-wave contours.

Atrial Function↗
PubMed2005

A fuzzy logic-based model for the multistage high-pressure inactivation of Lactococcus lactis ssp. cremoris MG 1363.

The high-pressure inactivation (200 to 600 MPa) of Lactococcus lactis ssp. cremoris MG 1363 suspended in milk buffer was investigated with both experimental and theoretical methods. The inactivation kinetics were characterised by the determination of the viable cell counts, cell counts of undamaged cells, LmrP activity, membrane integrity, and metabolic activity. Pressures between 200 and 600 MPa were applied, and pressure holding times were varied between 0 and 120 min. Experiments were carried out in milk buffer at pH values ranging between 4.0 and 6.5, and the effect of the addition of molar concentrations of NaCl and sucrose was furthermore determined. The inactivation curves of L. lactis, as characterised by viable cell counts, exhibited typical sigmoid asymmetric shapes. Generally, inactivation of the membrane transport system LmrP was the most sensitive indicator of pressure-induced sublethal injury. Furthermore, the metabolic activity was inactivated concomitant with or prior to the loss of viability. Membrane integrity was lost concomitant with or later than cell death. For example, treatments at 200 MPa for 60 min in milk buffer did not inactivate L. lactis, but fully inactivated LmrP activity and reduced the metabolic activity by 50%. The membrane integrity was unaffected. Thus, the assay systems chosen are suitable to dissect the multistep high-pressure inactivation of L. lactis ssp. cremoris MG 1363. A fuzzy logic model accounting for the specific knowledge on the multistep pressure inactivation and allowing the prediction of the quantities of sublethally damaged cells was formulated. Furthermore, the fuzzy model could be used to accurately predict pressure inactivation of L. lactis using conditions not taken into account in model generation. It consists of 160 rules accounting for several dependent and independent variables. The rules were generated automatically with fuzzy clustering methods and rule-oriented statistical analysis. The set is open for the integration of further knowledge-based rules. A very good overall agreement between measured and predicted values was obtained. Single, deviating results have been identified and can be explained to be measurement errors or model intrinsic deficiencies.

Animals↗
PubMed1993

Two-trait-locus linkage analysis: a powerful strategy for mapping complex genetic traits.

Recent advances in molecular biology have provided geneticists with ever-increasing numbers of highly polymorphic genetic markers that have made possible linkage mapping of loci responsible for many human diseases. However, nearly all diseases mapped to date follow clear Mendelian, single-locus segregation patterns. In contrast, many common familial diseases such as diabetes, psoriasis, several forms of cancer, and schizophrenia are familial and appear to have a genetic component but do not exhibit simple Mendelian transmission. More complex models are required to explain the genetics of these important diseases. In this paper, we explore two-trait-locus, two-marker-locus linkage analysis in which two trait loci are mapped simultaneously to separate genetic markers. We compare the utility of this approach to standard one-trait-locus, one-marker-locus linkage analysis with and without allowance for heterogeneity. We also compare the utility of the two-trait-locus, two-marker-locus analysis to two-trait-locus, one-marker-locus linkage analysis. For common diseases, pedigrees are often bilineal, with disease genes entering via two or more unrelated pedigree members. Since such pedigrees often are avoided in linkage studies, we also investigate the relative information content of unilineal and bilineal pedigrees. For the dominant-or-recessive and threshold models that we consider, we find that two-trait-locus, two-marker-locus linkage analysis can provide substantially more linkage information, as measured by expected maximum lod score, than standard one-trait-locus, one-marker-locus methods, even allowing for heterogeneity, while, for a dominant-or-dominant generating model, one-locus models that allow for heterogeneity extract essentially as much information as the two-trait-locus methods. For these three models, we also find that bilineal pedigrees provide sufficient linkage information to warrant their inclusion in such studies. We also discuss strategies for assessing the significance of the two linkages assumed in two-trait-locus, two-marker-locus models.

Chromosome Mapping↗
PubMed2005

Prediction of potential mushroom yield by visible and near-infrared spectroscopy using fresh phase II compost.

Potential mushroom (Agaricus bisporus) yield of phase II compost is determined by interactions of key quality parameters including dry matter, nitrogen dry matter, ammonia, pH, conductivity, thermophilic microorganisms, C : N ratio, fiber fractions, ash, and certain minerals. This study was aimed at generating robust visible and near-infrared (Vis-NIR) calibrations for predicting potential yield, using spectra from fresh phase II compost. Four compost comparative trials were carried out during the winter and summer months of 2001-2003, under controlled experimental conditions employing six commercially prepared composts, with eight replicate (8 bag) plots per treatment (48 x 8 = 384). The substrates were prepared by windrow or bunker phase I, followed by phase II production. The fresh samples were scanned for Vis-NIR (400-2498 nm) spectra, averaged, transformed, and regressed against the recorded yield by employing a modified partial least squares algorithm. The best calibration model generated from the database explained 84% of yield variation within the data set with a standard error of calibration of 13.75 kg/tonne of fresh compost. The model was successfully tested for robustness with yield results obtained from a validation trial, carried out under similar experimental conditions in early 2004, and the standard error of prediction was 18.21 kg/tonne, which was slightly higher than the mean experimental error (17.94 kg/tonne) of the trial. The accuracy of the model is acceptable for estimating potential yield by classifying phase II substrate as poor (180-220 kg), medium (220-260 kg), and high (260-300 kg) yielding compost. The yield prediction model is being transferred to a new instrument based at Loughgall for routine evaluation of commercial phase II samples.

Agaricales↗
PubMed2005

Determining localized garment insulation values from manikin studies: computational method and results.

The localized thermal insulation value expresses a garment's thermal resistance over the region which is covered by the garment, rather than over the entire surface of a subject or manikin. The determination of localized garment insulation values is critical to the development of high-resolution models of sensible heat exchange. A method is presented for determining and validating localized garment insulation values, based on whole-body insulation values (clo units) and using computer-aided design and thermal analysis software. Localized insulation values are presented for a catalog consisting of 106 garments and verified using computer-generated models. The values presented are suitable for use on volume element-based or surface element-based models of heat transfer involving clothed subjects.

Body Temperature Regulation↗
PubMed1990

Computer modeling of emergency medical system performance.

Emergency medical services (EMS) system managers face difficult problems when determining the need for system expansion and unit deployment. Information relevant to the decision is often limited and frequently not in a usable format. This lack of usable information often results in decisions that create less-than-optimal EMS systems. A constant search for greater efficiency prompted the development of a computer simulation model to analyze the current EMS system operated by the Tucson Fire Department and to provide statistical information on the effects of potential vehicle base locations on system performance. The simulation model generates data that reflect a variety of parameters necessary in base location analysis. Included in the performance statistics for each unit and for the entire system are indicators of unit use rates, minimum and maximum response times, and proportion of calls reached within the critical response time of eight minutes or less. The model has been carefully validated and used in unit redeployment and unit activation in Tucson, Arizona.

Arizona↗
PubMed1990

A polymerization model of chiasma interference and corresponding computer simulation.

A model of chiasma interference is proposed and simulated on a computer. The model uses random events and a polymerization reaction to regulate meiotic recombination between and along chromosomes. A computer simulation of the model generates distributions of crossovers per chromosome arm, position of events along the chromosome arm, distance between crossovers in two-event tetrads, and coincidence as a function of distance. Outputs from the simulation are compared to data from Saccharomyces cerevisiae and the X chromosome of Drosophila melanogaster. The simulation demonstrates that the proposed model can produce the regulation of recombination observed in both genetic and cytological experiments. While the model was quantitatively compared to data from only Drosophila and Saccharomyces, the regulation observed in these species is qualitatively similar to the regulation of recombination observed in other organisms.

Animals↗
PubMed1996

Determinants of myelosuppression in the treatment of non-small cell lung cancer with cisplatin-containing chemotherapy.

Data on 16 potential risk factors for myelosuppression were assessed in 134 patients who received either vindesine and cisplatin (VP) or mitomycin C, vindesine and cisplatin (MVP) for inoperable stage III or IV non-small cell lung cancer in a randomized trial. Determinant factors for myelosuppression were evaluated by using univariate analysis and the logistic regression model. Recursive partitioning and amalgamation (RPA) was also used to define patient subgroups frequently suffering from severe bone marrow toxicity. Overall, 33 (25%) of 134 patients experienced at least one episode of grade 4 leukopenia. In univariate analysis, age, body surface area, serum creatinine, and pretreatment hemoglobin concentration were associated with severe leukopenia. A multivariate analysis using the logistic regression method showed that only raised creatinine level was an independent predictor for grade 4 leukopenia (P = 0.049). The RPA model generated three distinct subgroups based on age, body surface area and regimen. The three subgroups were distinguished by the frequency of severe (grade 4) leukopenia (50%, 25%, and 2.4%, respectively) (P < 0.001). Grade 4 leukopenia occurred more frequently in patients in class 3 (age > or = 65 years and treatment with MVP). The RPA model was useful in identifying the risk factors for myelosuppression induced by cisplatin-based chemotherapy, and in defining patient subgroups with elevated risk of toxicity.

Adult↗
PubMed2026

Creating bottom-up RNA transfer vehicles from synthetic protein assemblies.

Evolution guides biological systems to populate ecological niches, with viruses among the most successful examples of this principle. Viruses evolved over billions of years to efficiently transfer genetic information. Although viruses are highly diverse, most have converged towards remarkable similarity in the size and shape of their capsids1,2. By contrast, generative models for protein design enable the creation of protein architectures that are absent from nature3-5. Here we investigate whether protein assemblies designed by artificial intelligence can be functionalized to construct nucleic acid transport vehicles that are independent of evolutionary trajectories. By combining natural protein domains with synthetic protein assemblies, we create more than 100 bottom-up RNA transfer vehicles with unique sizes and shapes. These vehicles surpass the RNA transfer efficiency of widely used delivery vehicles by several orders of magnitude. In addition, we demonstrate that their tropism can be programmed by incorporation of computationally designed peptide binders and use them to deliver therapeutically relevant cargo RNAs into a wide range of cellular models. We show the in vivo biodistribution of one of these vehicles in a mouse at near-single-cell resolution, confirm its safety, and use it to perform a gene-editing treatment strategy for Duchenne muscular dystrophy in patient-derived cells and a pig. Our work demonstrates how proteins created by generative artificial intelligence can be harnessed for the rational engineering of RNA transport systems with the desired properties by overcoming the limitations of natural protein diversity.

Journal Article↗
PubMed2002

Aberrant driving behaviour: homogeneity of a four-factor structure in samples differing in age and gender.

Four samples, representing a broad age range, were compared in confirmatory factor analyses with respect to a four-factor model of aberrant driving behaviour. With the restrictions imposed on the data by the model, an approximate fit was obtained for all four samples. Additional analyses, which tested equality of factor loadings and correlations for different age groups, also indicated that the model was a good fit. Separate analyses on male and female respondents yielded similar results. Although earlier results have shown that aberrant driving behaviours are differentially related to age and gender, the findings suggest that structural differences in relation to age and gender may be of minor importance. The four-factor model of aberrant driving behaviour sufficiently meets statistical criteria in a model-generating phase. In addition, it is an appropriate solution to apply on data obtained from respondents varying in age and gender.

Adult↗
PubMed2004

Structural conservation in the major facilitator superfamily as revealed by comparative modeling.

The structures of membrane transporters are still mostly unsolved. Only recently, the first two high-resolution structures of transporters of the major facilitator superfamily (MFS) were published. Despite the low sequence similarity of the two proteins involved, lactose permease and glycerol-3-phosphate transporter, the reported structures are highly similar. This leads to the hypothesis that all members of the MFS share a similar structure, regardless of their low sequence identity. To test this hypothesis, we generated models of two other members of the MFS, the Tn10-encoded metal-tetracycline/H(+) antiporter (TetAB) and the rat vesicular monoamine transporter (rVMAT2). The models are based on the two MFS structures and on experimental data. The models for both proteins are in good agreement with the data available and support the notion of a shared fold for all MFS proteins.

Animals↗
PubMed1997

Molecular structure and gas chromatographic retention behavior of the components of Ylang-Ylang oil.

Using quantitative structure-retention relationships (QSRR) methodologies the Kovats gas chromatographic retention indices for both apolar (DB-1) and polar (DB-Wax) columns for 48 compounds from Ylang-Ylang essential oil were empirically predicted from calculated and experimental data on molecular structure. Topological, geometric, and electronic descriptors were obtained for model generation. Relationships between descriptors and the retention data reported were established by linear multiple regression, giving equations that can be used to predict the Kovats indices for compounds present in essential oils, both in DB-1 and DB-Wax columns. Factor analysis was performed to interpret the meaning of the descriptors included in the models. The prediction model for the DB-1 column includes descriptors such as Randic's first-order connectivity index (1X), the molecular surface (MSA), the sum of the atomic charge on all the hydrogens (QH), Randic's third-order connectivity index (3X) and the molecular electronegativity (chi). The prediction model for the DB-Wax column includes the first three descriptors mentioned for the DB-1 column (1X, MSA and QH) and the most negative charge (MNC), the global softness (S), and the difference between Randic's and Kier and Hall's third-order connectivity indexes (3X-3XV).

Chromatography, Gas↗
PubMed2005

Modelling and validation of spectral reflectance for the colon.

The spectral reflectance of the colon is known to be affected by malignant and pre-malignant changes in the tissue. As part of long-term research on the derivation of diagnostically important parameters characterizing colon histology, we have investigated the effects of the normal histological variability on the remitted spectra. This paper presents a detailed optical model of the normal colon comprising mucosa, submucosa and the smooth muscle layer. Each layer is characterized by five variable histological parameters: the volume fraction of blood, the haemoglobin saturation, the size of the scattering particles, including collagen, the volume fraction of the scattering particles and the layer thickness, and three optical parameters: the anisotropy factor, the refractive index of the medium and the refractive index of the scattering particles. The paper specifies the parameter ranges corresponding to normal colon tissue, including some previously unpublished ones. Diffuse reflectance spectra were modelled using the Monte Carlo method. Validation of the model-generated spectra against measured spectra demonstrated that good correspondence was achieved between the two. The analysis of the effect of the individual histological parameters on the behaviour of the spectra has shown that the spectral variability originates mainly from changes in the mucosa. However, the submucosa and the muscle layer must be included in the model as they have a significant constant effect on the spectral reflectance above 600 nm. The nature of variations in the spectra also suggests that it may be possible to carry out model inversion and to recover parameters characterizing the colon from multi-spectral images. A preliminary study, in which the mucosal blood and collagen parameters were modified to reflect histopathological changes associated with colon cancer, has shown that the spectra predicted by our model resemble measured spectral reflectance of adenocarcinomas. This suggests that an extended model, which incorporates parameters corresponding to an abnormal colon, may be effective for differentiation between normal and cancerous tissues.

Algorithms↗
PubMed2004

Neuronal nicotinic acetylcholine receptor agonists: pharmacophores, evolutionary QSAR and 3D-QSAR models.

Neuronal nicotinic acetylcholine ion channel receptors (nAChRs) exist as several subtypes and are involved in a variety of functions and disorders of the central nervous system (CNS), such as Alzheimer's and Parkinson's diseases. The lack of reliable information on the 3D structure of nAChRs prompted us to focus efforts on pharmacophore and structure-affinity relationships (SAFIRs). The use of DISCO (DIStance COmparison) and Catalyst/HipHop led to the formulation of a pharmacophore that is made of three geometrically unrelated features: (i) an ammonium head involved in coulombic and/or H-bond interactions, (ii) a lone pair of a pyridine nitrogen or a carbonyl oxygen, as H-bond acceptor site, and (iii) a hydrophobic molecular region generally constituted by aliphatic cycles. The quantitative SAFIR (QSAFIR) study was carried out on about three hundred nicotinoid agonists, and coherent results were obtained from classical Hansch-type approach, 3D QSAFIRs, based on Comparative Molecular Field Analysis (CoMFA), and trade-off models generated by Multi-objective Genetic QSAR (MoQSAR), a novel evolutionary software that makes use of Genetic Programming (GP) and multi-objective optimization (MO). Within each congeneric series, Hansch-type equations revealed detrimental steric effects as the major factors modulating the receptor affinity, whereas CoMFA allowed us to merge progressively single-class models in a more global one, whose robustness was supported by crossvalidation, high prediction statistics and satisfactory predictions of the affinity data of a true external ligand set (r(2)(pred) = 0.796). Next, MoQSAR was used to analyze a data set of 58 highly active nicotinoids characterized by 56 descriptors, that are log P, MR and 54 low inter-correlated WHIM (Weighted Holistic Invariant Molecular) indices. Equivalent QSAFIR models, that represent different compromises between structural model complexity, fitting and internal model complexity, were found. Our attention was mostly engaged by a number of nonlinear QSAFIRs, which relate nAChR affinity with the log P and directional WHIM descriptors. The results reviewed herein show as QSAFIRs may helpfully complement the pharmacophores, thus enhancing the applicability of computer-aided methodologies in the field of nAChR agonists.

Hydrogen Bonding↗
PubMed2003

Modeling of corticosteroid pharmacogenomics in rat liver using gene microarrays.

Corticosteroid (CS) pharmacogenomics was studied using gene microarrays in rat liver. Methylprednisolone (MPL) was administered intravenously at 50 mg/kg. Rats were sacrificed and liver excised at 17 time points over 72 h. RNAs from individual livers were used to query Affymetrix GeneChips that contain sequences for 8000 genes. Cluster analysis revealed six temporal patterns consisting of 197 CS-responsive probes representing 143 genes. Based on our fifth-generation model of CS pharmacokinetics/pharmacodynamics (PK/PD), mechanistic models were developed to describe the time pattern for each CS-responsive gene. Two clusters showed increased expression with different effect duration. PK/PD models assuming CS stimulation of mRNA synthesis were applied. Another two clusters showed an initial decline followed by delayed increase, suggesting two mechanisms might be involved jointly. The initial suppression was captured by CS inhibition of mRNA synthesis or stimulation of degradation. CS may also stimulate the production of a biosignal (transcription factors or other hormones), which can cause secondary induction of the target mRNA. One cluster showed a very abrupt increase in message followed by rapid decrease. These genes were lymphocytic in origin and were modeled combining the fast gene induction effect of CS in lymphoid cells and its direct lymphocyte trafficking effect. Another cluster showed reduction persisting for 18 h, which was described by CS inhibition of mRNA synthesis. Our results reveal the marked diversity of genes regulated by CS via a limited array of mechanisms. These PK/PD models provide quantitation of CS pharmacogenomics and new hypotheses regarding understanding of diverse mechanisms of CS receptor-gene mediated action.

Animals↗
PubMed2006

The role of angiotensin receptor-1 blockade on electromechanical changes induced by left ventricular hypertrophy and its regression.

OBJECTIVE: The aims of this study were to: i) investigate the role of angiotensin in mediating changes to myocardial electromechanical properties during the development and regression of left ventricular hypertrophy (LVH) generated by constriction of the thoracic aorta; ii) identify any role of angiotensin-1 receptor blockade on ameliorating changes to these electromechanical properties. METHODS: LVH was induced in guinea-pigs by constricting the ascending aorta (AC groups). After 42+/-3 days, the constriction was either removed or left in place. Following the second operation animals were fed losartan (10 mg x kg(-1) x day(-1)) or saline for 42+/-3 days. Sham-operated animals served as controls. In other groups, LVH was generated by subcutaneous angiotensin II (200 ng x kg(-1) x min(-1)) infusion for 42+/-3 days with or without losartan administration (AT groups), and compared to animals undergoing aortic constriction for a similar period. Electromechanical changes were recorded in isolated left ventricular myocardial preparations. RESULTS: Wet and dry heart-to-body weight ratios (HBR) increased significantly in the AC and AT models compared to control. Losartan prevented the increase of HBR in the AT group. Removal of the constriction allowed LVH to regress to control. The force-frequency relationship was reduced in both models and recovered fully on regression. However, the two models generated different electrophysiological changes: in the AC group, longitudinal conduction velocity was reduced and transverse conduction increased, with a consequent reduction of the anisotropic conduction ratio. On regression recovery was only partial; action potential duration was prolonged and did not recover. In the AT group, electrophysiological changes were limited: only an increase of transverse conduction and a reduction of the anisotropic conduction ratio were observed. Losartan had no effect on HBR or electromechanical variables in the aortic constricted animals, nor did it affect the extent of recovery in animals with regression of LVH. CONCLUSIONS: The electromechanical changes to hypertrophied myocardium are different in these two models of LVH. Moreover, losartan was ineffective in modulating the consequences of hypertrophy induced by constriction of the thoracic aorta.

Angiotensin II↗
PubMed2006

Using ecological-niche modeling as a conservation tool for freshwater species: live-bearing fishes in central Mexico.

Ecological-niche modeling is an important tool for conservation assessment of terrestrial species; however, its applicability has been poorly explored in the aquatic realm. Goodeines are a monophyletic group of viviparous freshwater fishes that are well known in central Mexico, with 41 species in 19 genera. Given the number of threats to biodiversity in the region, goodeines represent an excellent model with which to test novel conservation approaches. We assessed the conservation status of the goodeines (37 species), based on their potential distributions predicted by ecological-niche models generated with the genetic algorithm for rule-set prediction (GARP). Predictions of species' distributions performed well in six out of eight species for which sufficient information was available to perform estimations of the area under the curve (AUC) in receiver operating characteristic plots. Extensive field surveys conducted in recent years in most cases confirm the models' predictions. Species richness exhibited a nested pattern, in which the number of species increased toward the center of the distribution of the group. At the basin level, the Río Ameca Basin had the highest number of species (11), chiefly because of the high number of microendemic species (6). Human activities within water bodies (e.g., extensive aquaculture) and drainages (e.g., agriculture, ranching, industrial activities) have affected most goodeines severely, given the deleterious effects of pollution and introductions of exotic species, such as carp (Cyprinus carpio, Ctenopharingodon idella) and tilapia (Oreochromis spp.). Our results paint a pessimistic picture for the long-term survival of many goodeines in their natural environment, and realistic conservation measures are complex and would require immediate protection of specific areas that we have identified. Ecological-niche modeling is a suitable tool for conservation assessment of freshwater species, but availability of environmental information on aquatic systems (e.g., temperature, water speed, pH, oxygen concentration) would improve distributional predictions.

Algorithms↗