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PubMed1998

A comparison of neural network models for the prediction of the cost of care for acute coronary syndrome patients.

Acute coronary syndromes have remained the focus of many clinical economic studies due to the increasing prevalence of the disease and the tightening of cost controls. An accurate descriptive cost model for this population would be a valuable tool for clinical researchers. With such a model, the relative importance of different factors upon the total cost of care could be determined through computer simulation. This study explored the use of different neural network architectures in creating a descriptive cost model. This was a difficult problem in that the costs span 3 orders of magnitude but the output variable of the neural network must be restricted to the range 0-1. Models that used logarithmic transformations and multiple modular networks were created and analyzed. It was found that the model with a single network and logarithmic transformation performed significantly better than other more complicated networks.

Coronary Disease↗
PubMed1997

Induction of glutathione depletion, p53 protein accumulation and cellular transformation by tetrachlorohydroquinone, a toxic metabolite of pentachlorophenol.

Glutathione (GSH) conjugate formation with tetrachlorohydroquione (TCHQ) and the GSH content in vivo were measured by capillary zone electrophoresis. A more than 60% depletion of GSH content was found in liver tissue of mice treated with TCHQ. In addition, p53 protein accumulation and DNA fragmentation was induced by TCHQ. A two-stage model of chemical transformation of mouse embryonic fibroblasts was used to elucidate the transformation activity of TCHQ in vitro, and a 33% foci formation efficiency was found at the concentration of 5 microM. GSH depletion caused by TCHQ could abolish the protective ability of the cell against reactive oxygen species provided by GSH. When DNA was damaged, p53 protein accumulated in the nucleus and, in the case of severe damage, initiated apoptosis. TCHQ's ability to cause GSH depletion and DNA damage may play a role in the cytotoxic and genotoxic properties of its metabolic precursor, PCP.

3T3 Cells↗
PubMed2005

Intraventricular administration of hepatocyte growth factor treats mouse communicating hydrocephalus induced by transforming growth factor beta1.

Communicating hydrocephalus may occur spontaneously in elderly patients or occur as a complication of meningitis or intracranial hemorrhage, typically as a result of fibrosis along the route of cerebrospinal fluid (CSF) flow. Hepatocyte growth factor (HGF) has anti-fibrotic properties and is a promising candidate for the treatment of various fibrotic diseases. Thus, the goal of this study was to examine the effect of exogenous HGF (30 microg of human recombinant (hr) HGF intraventricularly for 7 or 14 days) in a model of hr transforming growth factor beta1-induced communicating hydrocephalus in C57BL/6 mice. HGF treatment resulted in a reduction of ventriculomegaly, as demonstrated by magnetic resonance imaging, and improved spatial memory. Further, ink passage test demonstrated improvement of normalized CSF in flow in mice receiving HGF treatment as opposed to delayed CSF flow in the hydrocephalic mice at baseline. Finally, histological examination in hydrocephalic mice undergoing HGF treatment revealed reduction of collagen fibers in the meninges and normalization of their structures. These results indicate that exogenous HGF may be of utility in the treatment of hydrocephalus in humans.

Animals↗
PubMed2003

Efficient transformation of Medicago truncatula cv. Jemalong using the hypervirulent Agrobacterium tumefaciens strain AGL1.

The efficiency of Agrobacterium tumefaciens transformation of the model legume Medicago truncatula cv. Jemalong (genotype 2HA) was evaluated for strains LBA 4404, C58pMP90, C58pGV2260 and AGL1. Binary vectors carrying promoter- gus/ gfp reporter gene fusions and the nptII gene as selectable marker were used for plant in vitro transformation/regeneration. The highest transformation efficiency was obtained with the disarmed hypervirulent strain AGL1 (Ti plasmid TiBo542), for which the percentage of explants forming kanamycin (Km)-resistant calli was double that obtained with each of the other three strains. In addition, we were able to reduce the time necessary for plant regeneration using AGL1, with 24% of the explants generating Km-resistant transgenic plantlets within only 4-5 months of culture. Transgene expression in planta was analysed and found to be conserved in the T(1) descendents.

Agrobacterium tumefaciens↗
PubMed2004

Prognostic meta-signature of breast cancer developed by two-stage mixture modeling of microarray data.

BACKGROUND: An increasing number of studies have profiled tumor specimens using distinct microarray platforms and analysis techniques. With the accumulating amount of microarray data, one of the most intriguing yet challenging tasks is to develop robust statistical models to integrate the findings. RESULTS: By applying a two-stage Bayesian mixture modeling strategy, we were able to assimilate and analyze four independent microarray studies to derive an inter-study validated "meta-signature" associated with breast cancer prognosis. Combining multiple studies (n = 305 samples) on a common probability scale, we developed a 90-gene meta-signature, which strongly associated with survival in breast cancer patients. Given the set of independent studies using different microarray platforms which included spotted cDNAs, Affymetrix GeneChip, and inkjet oligonucleotides, the individually identified classifiers yielded gene sets predictive of survival in each study cohort. The study-specific gene signatures, however, had minimal overlap with each other, and performed poorly in pairwise cross-validation. The meta-signature, on the other hand, accommodated such heterogeneity and achieved comparable or better prognostic performance when compared with the individual signatures. Further by comparing to a global standardization method, the mixture model based data transformation demonstrated superior properties for data integration and provided solid basis for building classifiers at the second stage. Functional annotation revealed that genes involved in cell cycle and signal transduction activities were over-represented in the meta-signature. CONCLUSION: The mixture modeling approach unifies disparate gene expression data on a common probability scale allowing for robust, inter-study validated prognostic signatures to be obtained. With the emerging utility of microarrays for cancer prognosis, it will be important to establish paradigms to meta-analyze disparate gene expression data for prognostic signatures of potential clinical use.

Bayes Theorem↗
PubMed2004

Insights into the molecular mechanism of chronic fibrosis: the role of connective tissue growth factor in scleroderma.

Connective tissue growth factor (CCN2), a member of the CCN family of proteins, is a cysteine-rich matricellular protein. Connective tissue growth factor is not normally expressed in dermal fibroblasts unless induced. The most potent inducer of connective tissue growth factor thus far identified is transforming growth factor beta. Connective tissue growth factor, however, is constitutively overexpressed by fibroblasts present in skin fibrotic lesions, including scleroderma. The overexpression of connective tissue growth factor present in fibrotic lesions contributes to the phenotype of scleroderma in that connective tissue growth factor promotes matrix deposition, and fibroblast adhesion and proliferation. In animal models, whereas either transforming growth factor beta or connective tissue growth factor alone produce only a transient fibrotic response, connective tissue growth factor and transforming growth factor beta act together to promote sustained fibrosis. Thus the constitutive overexpression of connective tissue growth factor by fibroblasts present in fibrotic lesions would be expected to contribute directly to chronic, persistent fibrosis. This review discusses recent information regarding insights into connective tissue growth factor biology and, using scleroderma as a model system, the part connective tissue growth factor might play in fibrotic disease.

Animals↗
PubMed1986

Are we on the brink of a major transformation of clinical method?

The traditional clinical method, which has served medicine well for over 100 years, had its origins in the integration of physical examination with morbid anatomy in early 19th-century France. Now this method is showing signs of failing to meet some contemporary needs. In particular, there is no means for understanding the inner experience of patients. Previous models of a transformed method have not grappled with the problem of validation. Data on the inner experience of patients are not open to empiric validation in the same way as clinical data. The process of understanding the meaning of an illness is not, therefore, scientific in the conventional sense. There are, none the less, rigorous methods for validating the results of this form of inquiry, notably those of phenomenology. A transformed method should aim to understand the meaning of an illness for the patient as well as provide a clinical diagnosis. The transformation will require a change in the epistemology of medicine and an educational process that encourages reflection and growth of self-knowledge.

Adult↗
PubMed2004

The burgeoning field of statistical phylogeography.

In the newly emerging field of statistical phylogeography, consideration of the stochastic nature of genetic processes and explicit reference to theoretical expectations under various models has dramatically transformed how historical processes are studied. Rather than being restricted to ad hoc explanations for observed patterns of genetic variation, assessments about the underlying evolutionary processes are now based on statistical tests of various hypotheses, as well as estimates of the parameters specified by the models. A wide range of demographical and biogeographical processes can be accommodated by these new analytical approaches, providing biologically more realistic models. Because of these advances, statistical phylogeography can provide unprecedented insights about a species' history, including decisive information about the factors that shape patterns of genetic variation, species distributions, and speciation. However, to improve our understanding of such processes, a critical examination and appreciation of the inherent difficulties of historical inference and challenges specific to testing phylogeographical hypotheses are essential. As the field of statistical phylogeography continues to take shape many difficulties have been resolved. Nonetheless, careful attention to the complexities of testing historical hypotheses and further theoretical developments are essential to improving the accuracy of our conclusions about a species' history.

Demography↗
PubMed2006

Model-based analysis of dispersion curves using chirplets.

Time-frequency representations, like the spectrogram or the scalogram, are widely used to characterize dispersive waves. The resulting energy distributions, however, suffer from the uncertainty principle, which complicates the allocation of energy to individual propagation modes (especially when the dispersion curves of these modes are close to each other in the time-frequency domain). This research applies the chirplet as a tool to analyze dispersive wave signals based on a dispersion model. The chirplet transform, a generalization of both the wavelet and the short-time Fourier transform, enables the extraction of components of a signal with a particular instantaneous frequency and group delay. An adaptive algorithm identifies frequency regions for which quantitative statements can be made about an individual mode's energy, and employs chirplets (locally adapted to a dispersion curve model) to extract the (proportional) energy distribution of that single mode from a multimode dispersive wave signal. The effectiveness of this algorithm is demonstrated on a multimode synthetic Lamb wave signal for which the ground-truth energy distribution is known for each mode. Finally, the robustness of this algorithm is demonstrated on real, experimentally measured Lamb wave signals by an adaption of a correlation technique developed in previous research.

Journal Article↗
PubMed1990

Fourier transform infrared spectroscopy for the characterization of a model peptide-DNA interaction.

To better understand the structural basis of protein-DNA interactions, the conformational changes that accompany these interactions need to be described. In order to develop a methodological approach to this problem, Fourier transform infrared spectroscopy (FTIR) with derivative resolution enhancement has been used to identify conformational changes that occur when a 29-residue synthetic peptide binds nonspecifically to heterogeneous cellular DNA in aqueous solution. The peptide sequence was chosen de novo, in order to rationally design a peptide model that would allow the relationship between DNA binding and the stability of protein secondary structure to be studied. Peptide at a concentration of 100-200 microM produces 50% saturation of heterogeneous phage DNA sequences as well as of short synthetic oligonucleotides. FTIR spectra reveal significant changes in peptide and DNA upon binding. Second-derivative spectra resolve the amide I band of native peptide into components located at 1627 (beta-strand), 1658 (alpha-helix), and 1681 (turn or beta-strand) cm-1, with a distinct shoulder at 1647 cm-1 (disordered structure). Assignment of the 1681 cm-1 vibration to a turn conformation is supported by uv CD studies, which indicate significant amounts of turn structure in unbound peptide. Ultraviolet CD also confirms the existence of disordered and beta-strand regions in the free peptide. Upon interacting with DNA the band at 1681 cm-1 (turn) is no longer seen; a new band appears at 1675 cm-1; the 1627 cm-1 band (beta-strand) is considerably reduced in intensity; the position of the alpha-helical (1658 cm-1) component remains unchanged; the shoulder at 1647 cm-1 (disorder) disappears. The new vibration at 1675 cm-1 is characteristic of beta-strand structures. The asymmetric stretch (vAS) of the DNA phosphates shifts from 1223 (unbound) to 1229 cm-1 (bound); the relative intensities of vAS and the PO2- symmetric stretch (vS) are altered upon peptide binding.(ABSTRACT TRUNCATED AT 400 WORDS)

Base Sequence↗
PubMed1979

A nonlinear model for studying oscillations in the blood pressure control system.

The idea that physiological systems sometimes include oscillations as part of their control function is a relatively new idea; the paper discusses the role of such oscillations in the regulation of arterial blood pressure and how they can be studied by modelling techniques. A nonlinear model is proposed which can be related directly to the physiology. This is seen as an important step because mainly previous studies of biological oscillations have used lumped equations, e.g. the Van der Pol equation, which do not possess the property. On the basis of the model, the oscillatory behaviour of the blood pressure control system is analysed by the application of the dual input describing function technique, a powerful analytical method which has wide application to the study of nonlinear oscillatory phenomena in physiology. The final section of the paper considers the digital simulation of the model by Z transform techniques and how the simulation can be used to study the interaction of respiratory and blood pressure control systems.

Blood Pressure↗
PubMedDate not supplied

[Modeling of daily mortality in the Autonomous Community of Madrid (1986-1991)].

OBJECTIVE: To describe, estimate and model trends and seasonal variations in daily mortality in the Comunidad of Madrid, Spain. METHODS: Overall mortality rate, as well as gender, age and cause-specific mortality rates between january 1, 1986 and december 31, 1991 were analyzed. A cyclic pattern was detected using fast Fourier transform. Mortality was modelled using ARIMA stochastic models and Poisson regression models. RESULTS: Spectral analysis detected two statistically significant periodic components (winter-summer). Winter peak was related mainly to an excess in cardiovascular diseases in women aged 65 and over, as well as with cardiovascular, respiratory and digestive diseases in men aged 45 and over. The summer peak was related with women, aged 65 and over with cerebrovascular diseases as the cause of death. CONCLUSIONS: The two cycles detected support the hypothesis of an association between mortality and environmental factors.

Adolescent↗
PubMed2004

Fuzzy pharmacophore models from molecular alignments for correlation-vector-based virtual screening.

A pharmacophore-based approach for compiling focused screening libraries is presented. It integrates information from three-dimensional molecular alignments into correlation vector-based database screening. The pharmacophore model is represented by a number of spheres of Gaussian-distributed feature densities. Different degrees of "fuzziness" can be introduced to influence the model's resolution. Transformation of this pharmacophore representation into a correlation vector results in a vector of feature probabilities which can be utilized for rapid virtual screening of compound databases or virtual libraries. The approach was validated by retrospective screening for cyclooxygenase 2 (COX-2) and thrombin ligands. A variety of models with different degrees of fuzziness were calculated and tested for both classes of molecules. Best performance was obtained with pharmacophore models reflecting an intermediate degree of fuzziness, yielding an enrichment factor of up to 39 for the first 1% of the ranked database. Appropriately weighted fuzzy pharmacophore models performed better in retrospective screening than similarity searching using only a single query molecule. The new pharmacophore method was shown to complement existing approaches.

Crystallography, X-Ray↗
PubMed2005

Guided-MLESAC: faster image transform estimation by using matching priors.

MLESAC is an established algorithm for maximum-likelihood estimation by random sampling consensus, devised for computing multiview entities like the fundamental matrix from correspondences between image features. A shortcoming of the method is that it assumes that little is known about the prior probabilities of the validities of the correspondences. This paper explains the consequences of that omission and describes how the algorithm's theoretical standing and practical performance can be enhanced by deriving estimates of these prior probabilities. Using the priors in guided-MLESAC is found to give an order of magnitude speed increase for problems where the correspondences are described by one image transformation and clutter. This paper describes two further modifications to guided-MLESAC. The first shows how all putative matches, ratherthan just the best, from a particularfeature can be taken forward into the sampling stage, albeit at the expense of additional computation. The second suggests how to propagate the output from one frame forward to successive frames. The additional information makes guided-MLESAC computationally realistic at video-rates for correspondence sets modeled by two transformations and clutter.

Algorithms↗
PubMed1989

Suppression of transformation and immortality in human/Chinese hamster fibroblast hybrids--a model for suppressor gene isolation.

Somatic cell hybrids were produced by fusion of normal human (foreskin) fibroblasts and a transformed Chinese hamster fibroblast line V79-8. Overall, approximately 30% of hybrid clones showed stable reversion to normal morphology and growth control in vitro as shown by serum and anchorage dependence. In one-third of these clones, senescence was observed after a number of generations similar to that required for the human fibroblast parent cells to senesce. The remainder appear to be immortal. Normal human chromosomes can therefore restore growth control with or without finite life-span to this transformed cell. V79 cells were found to be transfectable at an efficiency compatible with detection of single-copy gene transfer from genomic DNA. Furthermore, these cells were exceptionally sensitive to negative ("suicide") selection. Taken together, our data suggest that the V79 line represents an ideal system for isolation of human tumour suppressor genes.

Animals↗
PubMed2004

High-frequency transformation of undeveloped plastids in tobacco suspension cells.

Although leaf chloroplast transformation technology was developed more than a decade ago, no reports exist of stable transformation of undeveloped plastids or other specialized plastid types, such as proplastids, etioplasts, or amyloplasts. In this work we report development of a dark-grown tobacco suspension cell model system to investigate the transformation potential of undeveloped plastids. Electron microscope analysis confirmed that the suspension cells carry plastids that are significantly smaller (approximately 50-fold less in volume) and have a very different subcellular localization and developmental state than leaf cell chloroplasts. Using antibiotic selection in the light, we demonstrated that both plastid and nuclear transformation of these cell suspensions is efficient and reproducible, with plastid transformation frequency at least equal to that of leaf chloroplast transformation. Homoplasmic plastid transformants are readily obtained in cell colonies, or in regenerated plants, providing a more consistent and versatile model than the leaf transformation system. Because of the uniformity of the cell suspension model, we could further show that growth rate, selection scheme, particle size, and DNA amount influence the frequency of transformation. Our results indicate that the rate-limiting steps for nuclear and plastid transformation are different, and each must be optimized separately. The suspension cell system will be useful as a model for understanding transformation in those plant species that utilize dark-grown embryogenic cultures and for characterizing the steps that lead to homoplasmic plastid transformation.

Cell Nucleus↗
PubMedDate not supplied

[Thiamine: a mechanistic model of interaction with protein].

Mechanistic model of thiamine-binding protein functioning which is based on the potential role of prototropic groups and hydrophobic environment around 5-beta-hydroxyethyl substituent of ligand has been proposed. As a model the chemical transformations of thiamine and its structural O-acyl substituted analogues in the presence of ferricyanide and phosphatic buffer in pH range 7,2-7,8 were investigated. The oxidation to the thiochrome and thiochrome derivatives is first order in substrate and ferricyanide concentrations. It is found that the reciprocal of the pseudo-first-order rate constant increases in ferrocyanide concentration at the constant oxidant concentration. Rate constants and partition ratios for reaction of thiamine, O-benzoylthiamine, O-(4-nitrobenzoyl)thiamine, O-(2-norbornoyl) thiamine, O-(1-norbornoyl)thiamine, O-(1-adamantoyl) thiamine, O-(2-adamantoyl) thiamine, O-(5-methyl-1-adamantyl)acetylthiamine, O-(2-adamantyl)acetylthiamine, O-(1-adamantyl)acetylthiamine were determined. The acceleration effect of hydrophobic fragment of O-acyl substituent is attributed to the formation of neutral tricyclic form in the step followed by electron transfer to ferricyanide. Mechanistic implications for possible transformation of thiamine in neutral tricyclic form at interaction with thiamine-binding protein are discussed.

Hydrogen-Ion Concentration↗