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PubMedDate not supplied

4D-fingerprints, universal QSAR and QSPR descriptors.

An elusive goal in the field of chemoinformatics and molecular modeling has been the generation of a set of descriptors that, once calculated for a molecule, may be used in a wide variety of applications. Since such universal descriptors are generated free from external constraints, they are inherently independent of the data set in which they are employed. The realization of a set of universal descriptors would significantly streamline such chemoinformatics tasks as virtual high-throughout screening (VHTS) and toxicity profiling. The current study reports the derivation and validation of a potential set of universal descriptors, referred to as the 4D-fingerprints. The 4D-fingerprints are derived from the 4D-molecular similarity analysis. To evaluate the applicability of the 4D-fingerprints as universal descriptors, they are used to generate descriptive QSAR models for 5 independent training sets. Each of the training sets has been analyzed previously by several varying QSAR methods, and the results of the models generated using the 4D-fingerprints are compared to the results of the previous QSAR analyses. It was found that the models generated using the 4D-fingerprints are comparable in quality, based on statistical measures of fit and test set prediction, to the previously reported models for the other QSAR methods. This finding is particularly significant considering the 4D-fingerprints are generated independent of external constraints such as alignment, while the QSAR methods used for comparison all require an alignment analysis.

Anesthetics, General↗
PubMedDate not supplied

In vivo monitoring of pancreatic beta-cells in a transgenic mouse model.

We generated a transgenic mouse model (RIP-luc) for the in vivo monitoring of pancreatic islet mass and function in response to metabolic disease. Using the rat insulin promoter fused to firefly luciferase, and noninvasive technology to detect luciferase activity, we tracked changes in reporter signal during metabolic disease states and correlated the changes in luciferase signal with metabolic status of the mouse. Transgene expression was found to be specific to the pancreatic islets in this transgenic model. Basal transgene expression was tracked in male and female mice fed either a chow or a high-fat diet and in response to treatment with streptozotocin. Pancreatic bioluminescent signal increased in mice fed a high-fat diet compared with chow-fed animals. In a model of chemically induced diabetes, the bioluminescent signal decreased in accordance with the onset of diabetes and reduction of islet beta-cell number. Preliminary studies using islets transplanted from this transgenic model suggest that in vivo image analysis can also be used to monitor transplanted islet viability and survival in the host. This transgenic model is a useful tool for in vivo studies of pancreatic beta-cells and as a donor for islet transplantation studies.

Animals↗
PubMed2001

Laser-induced noninvasive vascular injury models in mice generate platelet- and coagulation-dependent thrombi.

A minimally invasive laser-induced injury model is described to study thrombus development in mice in vivo. The protocol involves focusing the beam of an argon-ion laser through a compound microscope on the vasculature of a mouse ear that is sufficiently thin such that blood flow can be visualized by intravital microscopy. Two distinct injury models have been established. The first involves direct laser illumination with a short, high-intensity pulse. In this case, thrombus formation is inhibited by the GPIIb/IIIa antagonist, G4120. However, the anticoagulants, hirulog, PPACK, and NapC2 have minimal effect. This indicates that thrombus development induced by this model mainly involves platelet interactions. The second model involves low-intensity laser illumination of mice injected with Rose Bengal dye to induce photochemical injury in the region of laser illumination. Thrombi generated by this latter procedure have a slower development and are inhibited by both anticoagulant and anti-platelet compounds.

Amino Acid Chloromethyl Ketones↗
PubMed1998

The use of computer-generated three-dimensional models in orbital reconstruction.

In this paper we describe the application of three-dimensional (3D) imaging and computer-generated models in the management of orbital deformity. The technique was found to be particularly useful in posttraumatic deformity and fibrous dysplasia involving the orbit. Further application was found in cases of radiation hypoplasia, high facial cleft, and facial atrophy. Funding restrictions necessitate appropriate selection of cases when using new and expensive 3D imaging rather than traditional and less expensive methods. To remain within a realistic budget only those patients who will clearly benefit from the third dimension compared with traditional methods of assessment and management should be selected. These include patients requiring precise reduction or secondary reconstruction in which there is a matched normal anatomical component for comparison. This application is also only beneficial where the planned reconstruction is dimensionally stable.

Adolescent↗
PubMed2001

Liver cell transplantation -- novel animal model for human hepatic viral infections.

AIM: To generate a model of human hepatitis B infection (HBV) in immunocompetent rats with chimeric human liver. METHODS AND RESULTS: Normal rats were tolerized to human hepatocytes by exposure to human hepatocytes at day 17 of gestation. We transplanted human hepatocytes and inoculated HBV into the rats after birth. Mixed lymphocytes assay, a measure for tolerance, indicated that animals fetally exposed to human hepatocytes developed tolerance to human hepatocytes. Spleen lymphocytes from tolerized animals did not proliferate when challenged with donor human hepatocytes. In contrast, control animals given saline fetally developed no tolerance to human hepatocytes. Tolerant animals with transplanted human hepatocytes were susceptible to HBV infection. Western blot analysis and immuno-histochemistry of liver sections from tolerized, HBV infected animals with transplanted human hepatocytes showed the presence of functioning human hepatocytes that synthesized human albumin, of which 30% were also positive for HB surface antigen and HBV DNA. The presence of covalent closed circular HBV DNA in the liver indicated active HBV viral replication. CONCLUSION: Tolerized rats with chimeric human livers can be infected with HBV and used as an animal model for HBV infection. Tolerized rats with chimeric human livers can also be used for generating models of other human hepatic viral diseases.

Animals↗
PubMed2005

From brainstem to cortex: computational models of saccade generation circuitry.

The brain circuitry of saccadic eye movements, from brainstem to cortex, has been extensively studied during the last 30 years. The wealth of data gathered allowed the conception of numerous computational models. These models proposed descriptions of the putative mechanisms generating this data, and, in turn, made predictions and helped to plan new experiments. In this article, we review the computational models of the five main brain regions involved in saccade generation: reticular formation saccadic burst generators, superior colliculus, cerebellum, basal ganglia and premotor cortical areas. We present the various topics these models are concerned with: location of the feedback loop, multimodal saccades, long-term adaptation, on the fly trajectory correction, strategy and metrics selection, short-term spatial memory, transformations between retinocentric and craniocentric reference frames, sequence learning, to name the principle ones. Our objective is to provide a global view of the whole system. Indeed, narrowing too much the modelled areas while trying to explain too much data is a recurrent problem that should be avoided. Moreover, beyond the multiple research topics remaining to be solved locally, questions regarding the operation of the whole structure can now be addressed by building on the existing models.

Animals↗
PubMed1977

A model of functional epistasis and linkage disequilibrium in populations with overlapping generations.

A model of functional epistasis is proposed in which it is assumed that coupling and repulsion genotypes differ in metabolic efficiency and thus in development time and net fecundity. The implications of this model are investigated for iteroparous populations with fluctuating rates of increase. It is found that the fluctuations in rate of increase can lead to large fluctuations in gamete frequency and D, the coefficient of linkage disequilibrium, but that D will almost always have a value of zero at some point during the populations' demographic cycle. Some of the model populations would be expected to be in a state of linkage disequilibrium only fleetingly: others would exhibit D-cycles interpretable as random fluctuation. Implications of the model for interpretations of existing data on linkage disequilibrium among enzyme loci in Drosophila are discussed.

Animals↗
PubMed2004

Methods for generating high-resolution structural models from electron microscope tomography data.

Reconstructed volumes generated by tilt-image electron-microscope tomography offer the best spatial resolution currently available for studying cell structures in situ. Analysis is often accomplished by creating surface models that delineate grayscale contrast boundaries. Here, we introduce a specialized and convenient sequence of segmentation operations for making such models that greatly improves their reliability and spatial resolution as compared to current approaches, providing a basis for making accurate measurements. To assess the reliability of the surface models, we introduce a spatial uncertainty measurement based on grayscale gradient scale length. The model generation and measurement methods are validated by applying them to synthetic data, and their utility is demonstrated by using them to characterize macromolecular architecture of active zone material at the frog's neuromuscular junction.

Computer Simulation↗
PubMed1977

Further characterization of Sendai virus DI-RNAs: a model for their generation.

Sendai virus DI-RNAs which contain complementary ends have been characterized as follows. First, the complementary ends of three DI-RNAs, although somewhat different in size (110-150 base pairs), contain sequences that are both identical to each other and to the 5' end of the nondefective (ND) genome. Second, almost all the sequences contained sequences that are both identical to each other and to the 5' end of the nondefective (ND) genome. Second, almost all the sequences contained in the DI-RNAs derive from sequences that are contiguous to the 5' end of the ND genome. The ND genome, on the other hand, does not contain any sequences that are complementary to its 5' end. A genetic map and a model for the generation of the Sendai DI-RNAs are presented.

Base Sequence↗
PubMed1985

Model of a pattern generator for locomotion in mammals.

This paper presents an analytic model of a limb pattern generator that can produce complex muscle activation patterns such as those shown to control the limbs of cats. The limb pattern generator is considered to have a tonic input and six outputs; this provides for flexion and extension of representative muscles for each of the three joints of the limb. The pattern generator functions as a community of labile synthesized relaxation oscillators that alters its output in response to input. This model was studied using electromyographic data from an experiment conducted on an acute postmammillary cat preparation. The results suggest that the limb pattern generator can be represented as three subsystems: an oscillator that produces the fundamental frequency of the output in response to the tonic signal, nonlinear shaping functions that mold the oscillator output into the basic complex pattern, and appropriate weighting functions that generate the muscle activity pattern from basic waveforms. The model can account for speed changes in locomotion with a relatively smooth change of system parameters. The pattern generator model is generative, amenable to simulation studies, and can be realized by a neural network.

Animals↗
PubMed2006

A dynamical model of subharmonic generation in ultrasonic infrared thermography.

Subharmonics are often observed in ultrasonic infrared thermography (UIR) system as samples are excited by ultrasonic transducers, and it is testified that, as the subharmonics appear, the detectability of cracks or defects in the sample is greatly enhanced in the UIR system. A dynamical model to explore the generation mechanism of the subharmonics and simulate the sample motion excited by an ultrasonic transducer in the UIR system is presented in this paper. In the model, the sample is continuously impacted by the transducer as the transducer is pushed to the sample by a constant force, in which the sample is simplified as a damped oscillator and the transducer is simplified as an active oscillator with constant frequency and amplitude. The impact process is also taken into account, in which the acting force is assumed to vary linearly during the impact process. A stable waveform of subharmonics in the sample can be obtained in appropriate conditions.

Algorithms↗
PubMed1995

The electric image in weakly electric fish: I. A data-based model of waveform generation in Gymnotus carapo.

Understanding how electrosensory images are generated and perceived in actively electrolocating fish requires the study of the characteristics of fish bodies as electric sources. This paper presents a model of Gymnotus carapo based on measurements of the electromotive force generated by the electric organ and the impedance of the passive tissues. A good agreement between simulated and experimentally recorded transcutaneous currents was obtained. Passive structures participate in the transformation of the electromotive force pattern into transcutaneous current profiles. These spatial filtering properties of the fish's body were investigated using the model. The shape of the transcutaneous current profiles depends on tissue resistance and on the geometry and size of the fish. Skin impedance was mainly resistive. The effect of skin resistance on the spatial filtering properties of the fish's body was theoretically analyzed. The model results show that generators in the abdominal and central regions produce most of the currents through the head. This suggests that the electric organ discharge (EOD), generated in the abdominal and central regions is critical for active electrolocation. In addition, the well-synchronized EOD components generated all along the fish produce large potentials in the far field. These components are probably involved in long-distance electrocommunication. Preliminary results of this work were published as a symposium abstract.

Animals↗
PubMed2002

A dynamical model of saccade generation in reading based on spatially distributed lexical processing.

The understanding of the control of eye movements has greatly benefited from the analysis of mathematical models. Currently most comprehensive models include sequential shifts of visual attention. Here we propose an alternative model of eye movement control, which includes three new principles: spatially distributed lexical processing, a separation of saccade timing from saccade target selection, and autonomous (random) generation of saccades with foveal inhibition. These three features provide a common control mechanism for fixations, refixations, and regressions. Consequently, the model is called SWIFT (Saccade-generation with inhibition by foveal targets). Results from numerical simulations are in good agreement with effects of word frequency on single-fixation, first-fixation, and gaze durations as well as fixation and word skipping probabilities in first-pass analysis. The model inherently produces complex eye movement patterns including refixations and regressions due to its underlying dynamical principles.

Computer Simulation↗
PubMed2004

Models for the generation of the embryonic body axes: ontogenetic and evolutionary aspects.

Coelenterates including hydra are assumed to be close to the last common ancestor before bilaterality evolved. Models based on local self-enhancement and long-range inhibition account for pattern formation and regeneration along this ancestral axis. The body of a hydra-like ancestor evolved into the brain and heart of higher organisms, accounting for the close relationship of both patterning processes. Bilateria require a long-extended organizing region to pattern their dorsoventral axis. Models reveal the difficulties in the generation of such a stripe-like organizer and account for different mechanisms realized in vertebrates and insects. Common pathways involved in hydra budding and in the formation of appendages in higher organisms suggest a possible link.

Animals↗
PubMed2006

The codon 72 polymorphism-specific effects of human p53 are absent in mouse cells: implications on generation of mouse models.

Human p53, unlike mouse p53, contains a polymorphic site at codon 72 in exon 4 encoding either an arginine amino acid (72R) or a proline residue (72P). The 72R form was shown to induce apoptosis better than the 72P form, partly owing to its ability to efficiently bind to the nuclear-export protein CRM1 and localize to the mitochondria. This polymorphism has also been associated with cancer predisposition and chemo-sensitivity. Further understanding of the in vivo significance of this polymorphism in carcinogenesis requires the generation of mouse models. We have thus evaluated if the polymorphism-specific effects of human p53 are retained in mouse cells. Though being transcriptionally active, both the human polymorphs were found to have lost their ability to differentially suppress growth and bind to CRM1 or MDM2 in mouse cells. Moreover, chimaeric proteins containing mouse exons 2-3 and human exons 4-11 have also lost the polymorphism-specific effects in human cells, suggesting that human exons 2-3 are important in regulating the polymorphism-specific effects. Furthermore, human p53 and the various chimaeric proteins were generally less effective in inhibiting growth of mouse cells compared to mouse p53, suggesting that mouse p53 is more potent than human p53 in suppressing growth, partly due to enhanced binding of MDM2 to human p53. The data together suggest that mouse cells may not provide an appropriate environment for the manifestation of the polymorphism-specific functional differences of human p53, and hence, cautions against the expression of full-length or chimaeric p53 proteins in mice to study the effects of the polymorphism.

Animals↗
PubMed2006

Generation of atomistic models of periodic mesoporous silica by kinetic Monte Carlo simulation of the synthesis of the material.

We have developed a molecular simulation method for the generation of realistic atomic-level models for periodic mesoporous silicas. Using simplified interaction potentials and simplified representations of the templating micelles, the simulation follows the reaction path of the hydrothermal synthesis and calcination of the silica material in a kinetic Monte Carlo (kMC) simulation. The only input to the simulation is the geometry of the micelle and the number of silicic acid monomers at the beginning of the synthesis. We simulated the adsorption properties of the PMS models using Grand Canonical Monte Carlo simulation. With use of MCM-41 materials of different pore sizes as a prototype material, experimental and simulated adsorption isotherms for nitrogen, ethane, and carbon dioxide were compared, showing good agreement between simulation and experiment.

Journal Article↗