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A mathematical model for the generation and control of a pH gradient in an immobilized enzyme system involving acid generation.

An optimal pH control technique has been developed for multistep enzymatic synthesis reactions where the optimal pH differs by several units for each step. This technique separates an acidic environment from a basic environment by the hydrolysis of urea within a thin layer of immobilized urease. With this technique, a two-step enzymatic reaction can take place simultaneously, in proximity to each other, and at their respective optimal pH. Because a reaction system involving an acid generation represents a more challenging test of this pH control technique, a number of factors that affect the generation of such a pH gradient are considered in this study. The mathematical model proposed is based on several simplifying assumptions and represents a first attempt to provide an analysis of this complex problem. The results show that, by choosing appropriate parameters, the pH control technique still can generate the desired pH gradient even if there is an acid-generating reaction in the system.

Acids↗

A dynamic and spatial model with migration generating the log-Gaussian field of population densities.

A spatial version of a dynamic population model leading to the lognormal distribution is defined. The model establishes relations between the joint spatial and temporal autocorrelation and biological concepts like environmental stochasticity, migration and strength of local density-regulation. The model is generalized to describe communities of species leading to a dynamic and spatial lognormal species abundance model with migration.

Animals↗

N-ethyl-N-nitrosourea-based generation of mouse models for mutant G protein-coupled receptors.

Chemical random mutagenesis techniques with the germ line supermutagen N-ethyl-N-nitrosourea (ENU) have been established to provide comprehensive collections of mouse models, which were then mined and analyzed in phenotype-driven studies. Here, we applied ENU mutagenesis in a high-throughput fashion for a gene-driven identification of new mutations. Selected members of the large superfamily of G protein-coupled receptors (GPCR), melanocortin type 3 (Mc3r) and type 4 (Mc4r) receptors, and the orphan chemoattractant receptor GPR33, were used as model targets to prove the feasibility of this approach. Parallel archives of DNA and sperm from mice mutagenized with ENU were screened for mutations in these GPCR, and in vitro assays served as a preselection step before in vitro fertilization was performed to generate the appropriate mouse model. For example, mouse models for inherited obesity were established by selecting fully or partially inactivating mutations in Mc4r. Our technology described herein has the potential to provide mouse models for a GPCR dysfunction of choice within <4 mo and can be extended to other gene classes of interest.

Alkylating Agents↗

A test of the Easterlin fertility model using income for two generations and a comparison with the Becker model.

An important dimension of Easterlin's seminal work on fertility is the hypothesis of intergenerational taste formation, or the relative income hypothesis. Previous estimates have not had data on income in two generations, so the estimated own-income effects may have had a downward bias. This article uses data with income from two generations to estimate the Easterlin model directly. Own income is still not positively significant. A simple single-equation test is developed to distinguish this model from a Becker intergenerational serially correlated endowments model that he claims is observationally equivalent. The test results favor the Becker formulation.

Female↗

Simple model designed to generate new crystal structures derived from a mother phase; application to molecular compounds.

The basic principles of a model predicting new lattices from a known crystal structure are described. The first of the two-step procedure consists of extracting one- or two-dimensional periodic fragments (PF) from the mother structure. In the second step, symmetry operators are added to the PFs in order to generate one or several new three-dimensional lattices consistent with the 230 space groups. Most of the examples are related to polymorphism, but relationships between racemic compounds and enantiomers, twinning and lamellar epitaxy phenomena are also exemplified.

Journal Article↗

3D-QSAR CoMFA studies on trypsin-like serine protease inhibitors: a comparative selectivity analysis.

A series of indole/benzoimidazole-5-carboxamidines have been reported to inhibit various trypsin-like serine proteases viz. uPA, tPA, factor Xa, thrombin, plasmin, and trypsin, which are involved in various types of pathophysiological conditions such as cancer progression, thrombosis etc. Inhibition of these protease enzymes may serve as therapeutic agents in various types of cancer as well serve as anticoagulant or antithrombotic agents. The dual inhibitory action may result in poor clinical candidates. 3D-QSAR models were generated for indole/benzoimidazole-5-carboxamidines using the CoMFA technique to study their selectivity trends toward various trypsin-like serine proteases. Molecular superimposition was carried out on the template structure using atom-based RMS fit method. The CoMFA models were established from the training set of 25-29 molecules and validated by predicting the activities of seven-eight test set molecules. The CoMFA models generated using steric and electrostatic fields for tPA, fXa, thrombin, plasmin, and trypsin inhibition exhibited better statistical significance than the CoMFA models generated using ClogP as an additional descriptor. Thus, the validated CoMFA models with steric and electrostatic fields were used to generate 3D contour maps, which may provide possible modification of molecules for better selectivity/activity. The present 3D-QSAR studies emphasize the selectivity trends of indole/benzoimidazole-5-carboxamidines, which may be obliging in designing novel selective serine protease inhibitors of therapeutic interest.

Amidines↗

A discriminative framework for detecting remote protein homologies.

A new method for detecting remote protein homologies is introduced and shown to perform well in classifying protein domains by SCOP superfamily. The method is a variant of support vector machines using a new kernel function. The kernel function is derived from a generative statistical model for a protein family, in this case a hidden Markov model. This general approach of combining generative models like HMMs with discriminative methods such as support vector machines may have applications in other areas of biosequence analysis as well.

Biometry↗

A new model for the generation of sympathetic nerve activity.

1. Sympathetic discharges from multifibre nerve recordings vary in their frequency of occurrence which displays both slow and fast rhythms and in their amplitude which reflects the number of activated fibres. It has been shown that the frequency of occurrence of these rhythms varies according to baroreceptor activity (via blood pressure and heart rate) while the number of activated fibres is independently affected by chemoreceptor activity. 2. A new model is proposed for the generation of sympathetic nerve activity by the central nervous system to account for these results. The upper layer of the model comprises two oscillators, a fast and a slow cycle frequency oscillator, with the balance and occurrence maintained by afferent inputs such as the baroreceptors. 3. It is hypothesized that two central oscillators impinge on a lower layer of the model influencing the number of activated fibres within each postganglionic sympathetic burst. This is independent of the frequency control and affected by separate afferent inputs such a chemoreceptors.

Animals↗

A model for the generation of synthetic intramuscular EMG signals to test decomposition algorithms.

As more and more intramuscular electromyogram (EMG) decomposition programs are being developed, there is a growing need for evaluating and comparing their performances. One way to achieve this goal is to generate synthetic EMG signals having known features. Features of interest are: the number of channels acquired (number of detection surfaces), the number of detected motor unit action potential (MUAP) trains, their time-varying firing rates, the degree of shape similarity among MUAPs belonging to the same motor unit (MU) or to different MUs, the degree of MUAP superposition, the MU activation intervals, the amount and type of additive noise. A model is proposed to generate one or more channels of intramuscular EMG starting from a library of real MUAPs represented in a 16-dimensional space using their Associated Hermite expansion. The MUAP shapes, regularity of repetition rate, degree of superposition, activation intervals, etc. may be time variable and are described quantitatively by a number of parameters which define a stochastic process (the model) with known statistical features. The desired amount of noise may be added to the synthetic signal which may then be processed by the decomposition algorithm under test to evaluate its capability of recovering the signal features.

Action Potentials↗

A model for the generation of low level chemiluminescence from microbiological growth media and its depletion by bacterial cells.

We present a model for the development of chemiluminescence (CL) in autoclaved liquid growth media, as they are used in microbiology for the culturing of microorganisms, or in other related Maillard systems. The model distinguishes between four different stages consisting of sugar fragmentation during heating, autooxidation of highly reducing fragmentation products, radical chain reactions leading to a peroxidation of the media, and finally the formation of excited states, energy transfer reactions and CL emission. The proposed model is also discussed in regard of a recently reported elimination of this CL in growing cultures of microorganisms and possible pathways for this interference are suggested.

Bacteria↗

A model for the generation of intra-uterine pressure in the human parturient uterus which demonstrates the critical role of the cervix.

A mathematical model is presented which describes the relationship between intrauterine pressure and uterine wall tension. Wall tension is evaluated in terms of muscular contraction in an active myometrium and the modulating effect of a passive, compliant cervix. Using a computer programme which simulates the recruitment of contractile elements in the uterine wall, it is possible to generate theoretical pressure waveforms. The effects on these waveforms produced by changing cervical properties are demonstrated and compared with observed phenomena. The physiological and clinical implications are evaluated.

Cervix Uteri↗

Nonlinear signal-processing model for signal generation in multilevel two-dimensional optical storage.

A two-dimensional optical storage (TwoDOS) format with binary modulation is being developed in which channel bits are arranged on a two-dimensional hexagonal lattice [W. M. J. Coene, in Optical Data Storage, Vol. 88 of OSA Trends in Optics and Photonics Series (Optical Society of America, Washington, D.C., 2003), pp. 90-92]. The aim is to increase the capacity by a factor of 2 and the data rate by a factor of 10 over third-generation Blu-ray Disc technology. Following a route similar to that used in one-dimensional conventional optical storage [Jpn. J. Appl. Phys. 42, 1074 (2003)] could lead to a further increase in capacity by the addition of another dimension to writing data, such as the use of multiple levels instead of the two levels (pit and land) used in the binary TwoDOS disk format. We present a nonlinear signal-processing model for signal waveform generation as a function of the M-ary channel symbols, as well as simulated signal readouts for multilevel TwoDOS.

Journal Article↗

A model for shape generation by strain and cell-cell adhesion in the epithelium of an arthropod leg segment.

We present a model for the energetic factors determining the most stable shape of a tubular epithelium such as the hypodermis of an arthropod leg segment. The model uses the analysis by Steinberg (1963) of rearrangement of cells in aggregates under the influence of differential adhesion, combining this analysis with the assumption that the epithelium behaves as an elastic sheet. The epithelium is assumed to consist of blocks of cells with different adhesive affinities, which remain unmixed in a quilt pattern. Rearrangement of cells within each block can adjust the shape of the tube by changing the shapes of the blocks. By means of such rearrangements the tube develops that shape which minimizes a free energy. The free energy is the difference between the energy of mechanical strain due to bending of the epithelium and the work of adhesion among cells. Minimization of the free energy for a cylindrical segment yields a scaling relation involving the length and radius of the segment. Leg segments of Drosophila conformed approximately to this relation, with deviations which suggest that a whole-limb pattern of adhesive affinities modulates the shaping effects of an adhesive pattern repeated in each leg segment. The model also predicts a transient deformation in an epithelium following a grafting operation. For example, deleting a slab of tissue from a tubular segment and reuniting the cut ends should produce a constriction of the tube at the host-graft junction. We propose that patterns of strain and adhesion can provide positional information which regulates subsequent development. Local increases in strain or adhesive disparity may stimulate mitoses; the resulting changes in distribution of cells will affect morphogenesis.

Animals↗

Realtime textured 3D-models for medical applications.

Realistic visualisation becomes more and more important in medicine. Whenever a patient individual 3D-model was generated the aim is to visualise the model as realistic as possible. We use 3D-models in our diagnostic and therapeutic tools for intraoperative visualisation of e.g. CT-scans. Most medical tools uses surface-rendering or volume-rendering for virtual visualisation. The coloration of a visualised model is normally done by using a convenient colour for each surface resp. volume. Our approach for 3D-models generated from motion in image series (e.g. videoendoscopes) is to add textures to the 3D-model. The main problem is, to handle the huge amount of videoimage-data (20Mb/sec.) and render the model in realtime.

Computer Simulation↗

Nonlinear mechanics of the inner ear and its relation to otoacoustic emissions: two steps on the way to a mathematical model of DPOAE generation.

Among clinical users of the registration of distortion product otoacoustic emissions (DPOAE), the understanding of the basic causality and interpretation of the phenomenon is not yet widely spread, nor is the expected influence of the middle ear and ear canal clear. On the other side, the effort in mathematical modeling of middle and inner ear structures is driven very far by now. We are convinced, though, that the essentials of an effect as DPOAE generation must be understandable from quite simple models. In a first step de Boer's one-dimensional model was adopted and expanded by a weak frictional and a weak elastic nonlinearity, respectively. By means of perturbation theory the weakly nonlinear problem is converted in an approximation series of linear problems. So it is solvable by the common methods of linear differential equations (DEs), above all the superposition principle can be used. At the same time a structure of causality is introduced: Sources for outgoing waves are in first order approximation formed by incoming waves, and so they can be localized. The calculations show clearly that of all six cubic distortions only the 2f(1) - f(2) term does have a source in its 'allowed' region and so can travel outward. We can use the calculated DPOAE to study the influence of middle ear, external ear canal and probe plug. Some problems remain: the weakly nonlinear model in first order does not give account for proper L(dp) = f(L(1), L(2)) and L(dp) = f(f(2)/f(1)) dependency, nor does it deliver additional sources or the effect of additional suppressor tones. In a second step, therefore, we replace de Boer's simple model basilar membrane (BM) by a doubly resonant, coupled tectorial/basilar membrane (TM/BM) system. By feedback now we introduce a strong nonlinearity, which we can mathematically care for by an iterative feedback loop. The algorithm shapes the incoming waves according to strong compressive nonlinearity. More relastic incoming waves yield better source terms, and after optimization of the mistuning function between TM and BM the model now is able to deliver qualitatively correct L(dp) (L(1),L(2)) and L(dp)(f(2)/f(1)) dependencies.

Basilar Membrane↗

A second generation transgenic mouse model expressing both hemoglobin S (HbS) and HbS-Antilles results in increased phenotypic severity.

We report on a second generation of transgenic mice produced by crossing a transgenic mouse line expressing high levels of human alpha and beta S chains (alpha H beta S [beta MDD]) with a line expressing human alpha and beta S-Antilles (beta SAnt). We hypothesized that mice expressing both hemoglobins (Hbs) would have a more severe phenotype because the reduced oxygen affinity and solubility of the beta S-Antilles might enhance the rate and extent of polymer formation. We obtained mice that expressed both beta S and beta S-Antilles. The doubly transgenic mice that are heterozygous for deletion of mouse beta Major (beta MD) occurred with reduced frequency and those that are homozygous for deletion of mouse beta Major (beta MDD) occurred at a much reduced frequency and suffered early mortality. Human alpha was 58% of all alpha globin for all animals, whereas beta S and beta S-Antilles were 34% and 28% of all beta globins for beta MD mice and 42% and 36% for beta MDD mice. Hematocrit, Hb, and mean corpuscular Hb were normal for all transgenic mice, but reticulocyte levels were higher for the doubly transgenic mice versus alpha H beta S [beta MDD] mice older than 30 days (10.0% +/- 1.0% v 4.3% +/- 0.4%; P < .001, mean +/- SE, n = 20 and n = 10, respectively) and control mice (3.9% +/- 0.4%). Reticulocytosis was more severe in mice less than 30 days old ( > 20% for alpha H beta S beta S-Ant[beta MDD] mice). The median mean corpuscular hemoglobin concentration of doubly transgenic mice was higher than that of alpha H beta S[beta MDD] mice with a variable number of very dense cells. Delay times for polymerization of Hb in red blood cells from alpha H beta S beta S-Ant[beta MDD] mice were shorter than those of alpha H beta S[beta MDD] mice, and there were fewer cells with delay times greater than 100 seconds. Urine-concentrating ability in control mice under ambient conditions is 2,846 +/- 294 mOsm and was reduced 30% to 1,958 +/- 240 mOsm, P < 4 x 10(-8) in all mice expressing both transgenes. We conclude that doubly transgenic mice have a more severe phenotype than either of the two parental lines. These mice may be suitable for validating therapeutic intervention in sickle cell disease.

Anemia, Sickle Cell↗