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PubMed1992

Stress distribution in a physical buttock model: effect of simulated bone geometry.

Mechanical stresses developed in the tissue during sitting or reclining could cause bedsores in paralyzed individuals. Cushions are usually prescribed to redistribute the stresses. Two two-dimensional physical models of the buttock were developed and used to study whether the stress distribution is different with round- and flat-base bone core geometries and to find out whether the relative cushion responses are dependent on loading direction and bone core geometries. In these models, PVC gel simulated the soft tissue and a wooden core simulated the bony prominence. One model had a round-base core and the other had a flat-base bone core. A grid etched on the model allowed strain measurements, and stress calculations. The sharp-base bone core model generated large regions of high shear stress during vertical and inclined loading. However, the round-base core produced maximum compressive stress during vertical loading. The relative cushion responses were dependent on bone core geometry and loading direction.

Air↗

PubMedDate not supplied

Molecular modeling approaches for the prediction of the nonspecific binding of drugs to hepatic microsomes.

Molecular modeling approaches for the prediction of the nonspecific binding of drugs to hepatic microsomes were examined using a published database of 56 compounds. Models generated were evaluated using an independent test set of 13 compounds. A pharmacophore approach identified structural features of drugs associated with nonspecific binding. A side-chain amino group and complementary hydrophobic domain were the principal features noted. The use of shape overlays, based on the pharmacophore, in conjunction with a chemical force field in the program ROCS, yielded discrimination between molecules classified as strong binders (experimental fraction unbound in microsomes<0.50) and those with a lower degree of binding (experimental fraction unbound in microsomes>0.50). In the initial data set of 56 molecules, 18 were classified as strong binders (on the basis of the above criteria), and all of those were recovered in the top 22 molecular hits from ROCS. Additionally, computationally generated values of log P were shown to provide a reasonable estimate of the fraction unbound in microsomes, providing the compounds were in their basic form at physiological pH.

Amino Acid Motifs↗

PubMed2004

Few amino acid positions in rpoB are associated with most of the rifampin resistance in Mycobacterium tuberculosis.

BACKGROUND: Mutations in rpoB, the gene encoding the beta subunit of DNA-dependent RNA polymerase, are associated with rifampin resistance in Mycobacterium tuberculosis. Several studies have been conducted where minimum inhibitory concentration (MIC, which is defined as the minimum concentration of the antibiotic in a given culture medium below which bacterial growth is not inhibited) of rifampin has been measured and partial DNA sequences have been determined for rpoB in different isolates of M. tuberculosis. However, no model has been constructed to predict rifampin resistance based on sequence information alone. Such a model might provide the basis for quantifying rifampin resistance status based exclusively on DNA sequence data and thus eliminate the requirements for time consuming culturing and antibiotic testing of clinical isolates. RESULTS: Sequence data for amino acid positions 511-533 of rpoB and associated MIC of rifampin for different isolates of M. tuberculosis were taken from studies examining rifampin resistance in clinical samples from New York City and throughout Japan. We used tree-based statistical methods and random forests to generate models of the relationships between rpoB amino acid sequence and rifampin resistance. The proportion of variance explained by a relatively simple tree-based cross-validated regression model involving two amino acid positions (526 and 531) is 0.679. The first partition in the data, based on position 531, results in groups that differ one hundredfold in mean MIC (1.596 micrograms/ml and 159.676 micrograms/ml). The subsequent partition based on position 526, the most variable in this region, results in a > 354-fold difference in MIC. When considered as a classification problem (susceptible or resistant), a cross-validated tree-based model correctly classified most (0.884) of the observations and was very similar to the regression model. Random forest analysis of the MIC data as a continuous variable, a regression problem, produced a model that explained 0.861 of the variance. The random forest analysis of the MIC data as discrete classes produced a model that correctly classified 0.942 of the observations with sensitivity of 0.958 and specificity of 0.885. CONCLUSIONS: Highly accurate regression and classification models of rifampin resistance can be made based on this short sequence region. Models may be better with improved (and consistent) measurements of MIC and more sequence data.

Amino Acids↗

PubMed1994

The importance of biological realism in dioxin risk assessment models.

Mechanistic mathematical models of hepatocarcinogenesis in the female rat were constructed to investigate possible relationships among the Ah, estrogen, and EGF receptors in TCDD hepatocarcinogenicity. Each model generates dose-response curves for the expression of biomarker liver proteins CYP1A1, CYP1A2, and residual plasma membrane EGF receptor consequent to exposure to TCDD. The shapes of the response curves were strongly dependent on the assumed mechanisms of constitutive expression of these proteins. Assuming a constant level of the hepatic Ah receptor, a sigmoidal dose-response of hepatic CYP1A1 to total liver TCDD was computed. However, inclusion of induction of the Ah receptor by TCDD in a physiologically realistic dosimetric model produced a linear low-dose response of CYP1A1. This behavior was computed to arise from the net effect of sublinear response of CYP1A1 mRNA to the concentration of the Ah-TCDD complex and supralinear response of the protein concentration to the mRNA level, illustrating the importance of biological realism in dose-response modeling. The dosimetric model also computed effects of TCDD on the hepatic estradiol concentration and consequent effects on the binding capacity of the EGF receptor and suggests plausible mechanisms for tumor promotion by TCDD. Setting circulating estradiol levels in the model to values typical of the male rat indicated possible sources of the differences in the responses of the EGF receptor and in development of tumors in the two sexes.

Animals↗

PubMed1997

Preliminary experience with medical applications of rapid prototyping by selective laser sintering.

Rapid prototyping techniques, originally developed for building components from computer aided designs in the motor industry, are now being applied in medicine to build models of human anatomy from high resolution multiplanar imaging data such a computed tomography (CT). The established technique of stereolithography and the more recent selective laser sintering (SLS), both build up an object layer by layer. Models have applications in surgical planning, for the design of customised implants and for training. Preliminary experience of using the SLS technique for medical applications is described, addressing questions regarding image processing, data transfer and manufacture. Pilot models, built from nylon, included two skills (a child with craniosynoslosis and an adult with hypertetorism) and a normal femur which was modelled for use in a bioengineering test of an artificial hip. The dimensions of the models were found to be in good agreement with the CT data from which they were built-for the child's skull the difference between the model and the CT data was less than 1.0 +/- 0.5 mm in each direction. Our experience showed that, with care, a combination of existing software packages may be used for data conversion. Ideally, image data of high spatial resolution should be used. The pilot models generated sufficient clinical interest for the technique to be pursued in the orthopaedic field.

Adult↗

PubMed2004

Nuclear-targeting of mutant huntingtin fragments produces Huntington's disease-like phenotypes in transgenic mice.

Huntington's disease (HD) results from the expansion of a glutamine repeat near the N-terminus of huntingtin (htt). At post-mortem, neurons in the central nervous system of patients have been found to accumulate N-terminal fragments of mutant htt in nuclear and cytoplasmic inclusions. This pathology has been reproduced in transgenic mice expressing the first 171 amino acids of htt with 82 glutamines along with losses of motoric function, hypoactivity and abbreviated life-span. The relative contributions of nuclear versus cytoplasmic mutant htt to the pathogenesis of disease have not been clarified. To examine whether pathogenic processes in the nucleus disproportionately contribute to disease features in vivo, we fused a nuclear localization signal (NLS) derived from atrophin-1 to the N-terminus of an N171-82Q construct. Two lines of mice (lines 8A and 61) that were identified expressed NLS-N171-82Q at comparable levels and developed phenotypes identical to our previously described HD-N171-82Q mice. Western blot and immunohistochemical analyses revealed that NLS-N171-82Q fragments accumulate in nuclear, but not cytoplasmic, compartments. These data suggest that disruption of nuclear processes may account for many of the disease phenotypes displayed in the mouse models generated by expressing mutant N-terminal fragments of htt.

Age Factors↗

PubMed2002

Monte Carlo modelling of the spectral reflectance of the human eye.

The interpretation of in vivo spectral reflectance measurements of the ocular fundus requires an accurate model of radiation transport within the eye. As well as considering the scattering and absorption processes, it is also necessary to account for appropriate histological variation. This variation results in experimentally measured spectra which vary, both with position in the eye, and between individuals. In this paper the results of a Monte Carlo simulation are presented. Three histological variables are considered: the RPE melanin concentration, the choriodal haemoglobin concentration and the choroidal melanin concentration. By considering these three variables, it is possible to generate model spectra which agree well with in vivo experimental measurements of the nasal fundus. The model has implications for the problem of extracting histological parameters from spectral reflectance measurements. These implications are discussed and a novel approach to interpretation of images of the ocular fundus suggested.

Algorithms↗

PubMed1996

Recognition-by-parts: a computational approach to human learning and generalization of shapes.

In this paper human pattern recognition is modeled in terms of how human observers learn to describe patterns in terms of their perceived parts, their unary (part) and binary (relational) attributes and the way in which such attribute states "evidence' different classes of shapes. This approach, originally developed in the area of computer vision, is concerned with algorithms which enable the learning of shape descriptions from examples and the classification of new data (generalization) efficiently and accurately. An object in such an "evidence-based' system is represented by a set of rules, where each rule provides a certain amount of evidence for each object class in the database. The accumulated class evidence over all activated rules can then be used to determine the classification probability. We have examined how well this model reflects human perception by training observers to classify compound Gabor patterns and then testing them with versions of such patterns which were segmented (gray-level transformed) versions of the original training set. If the observers were to construct rules to define each pattern class in terms of perceived parts and their relations, then it should be expected that classification performance would generalize to these new patterns from the original set. Results confirm this hypothesis and the specific feature extraction, learning and rule generation model used to predict performance.

Attention↗

PubMed1993

Predictors of falls among right-hemisphere stroke patients in the rehabilitation setting.

The purpose of the study was to examine neuropsychological and general medical risk factors for falls among a high-risk patient group in an inpatient rehabilitation setting. The sample consisted of 32 nonambulatory males who had sustained a right-hemisphere stroke (R-CVA). The Fall Assessment Questionnaire (FAQ) was introduced as a measure of known risk factors for falls in an inpatient setting. Neuropsychological assessment included measures of attention, perceptual deficits, hemispatial neglect, and impulsivity. A predictive model generated using multiple regression found that the FAQ combined with a measure of behavioral impulsivity successfully predicted fall status in 78% to 81% of cases, depending upon the cutting score used (p < .003). R-CVA patients who fell were more impulsive (p < .001) and received higher FAQ scores (p < .001). Perceptual deficit as measured by the Rey-Osterreith Complex Figure and general inattention as measured by Digit Span (reverse) were associated with falls (p < .04); however, they did not add to the model predicting which of the R-CVA patients would fall. It was suggested that impulsivity may act as an important mediating factor in determining individual risk for fall.

Accidental Falls↗

PubMedDate not supplied

Ligand-based molecular modeling study on a chemically diverse series of cholecystokinin-B/gastrin receptor antagonists: generation of predictive model.

Pharmacophore hypotheses were developed for six structurally diverse series of cholecystokinin-B/gastrin receptor (CCK-BR) antagonists. A training set consisting of 33 compounds was carefully selected. The activity spread of the training set molecules was from 0.1 to 2100 nM. The most predictive pharmacophore model (hypothesis 1), consisting of four features, namely, two hydrogen bond donors, one hydrophobic aliphatic, and one hydrophobic aromatic feature, had a correlation (r) of 0.884 and a root-mean-square deviation of 1.1526, and the cost difference between null cost and fixed cost was 81.5 bits. The model was validated on a test set consisting of six different series of 27 structurally diverse compounds and performed well in classifying active and inactive molecules correctly. This validation approach provides confidence in the utility of the predictive pharmacophore model developed in this work as a 3D query tool in the virtual screening of drug-like molecules to retrieve new chemical entities as potent CCK-BR antagonists. The model can also be used to predict the biological activities of compounds prior to their costly and time-consuming synthesis.

Algorithms↗

PubMed1991

Models for the generation of the binaural difference response.

Two simple models are examined in order to explain the observation that a portion of the binaural-evoked response is less than the sum of monaural-evoked responses in human and animal subjects. The sum of monaural responses minus the binaural response is called the binaural difference (BD). Each model acts on binaural input signals and applies a single memoryless nonlinearity. One model (IE) applies a rectifying nonlinearity to the difference of input signals, while the other (EE) applies a compressive nonlinearity to the sum of input signals. These models are suggested by properties of inhibitory-excitatory (IE) and excitatory-excitatory (EE) neurons of the auditory brainstem. Parameters can be found that enable each model to produce a ratio of BD to summed monaural response which is invariant with input stimulus level. The IE model, but not the EE model, has a BD whose level is linearly related to input stimulus level.

Animals↗

PubMed1998

Stochastic feedback and the regulation of biological rhythms.

We propose a general approach to the question of how biological rhythms spontaneously self-regulate, based on the concept of "stochastic feedback". We illustrate this approach by considering at a coarse-grained level the neuroautonomic regulation of the heart rate. The model generates complex dynamics and successfully acounts for key characteristics of cardiac variability, including the l/f power spectrum, the functional form and scaling of the distribution of variations, and correlations in the Fourier phases indicating nonlinear dynamics.

Circadian Rhythm↗

PubMed1985

Versatile expression vectors for high-level synthesis of cloned gene products in Escherichia coli.

We have constructed a set of expression vectors which contain synthetic DNA sequences comprising a computer-generated model ribosomal binding site located downstream from the tightly regulated phage lambda pL. promoter. These vectors have been used in several laboratories to produce significant amounts of eukaryotic and prokaryotic gene products in Escherichia coli, either as fusion proteins (with two to nine extra N-terminal amino acids) or as proteins containing the naturally occurring amino terminus. For inserting DNA sequences downstream of an initiation codon, we used synthetic oligonucleotides to introduce multiple-use restriction sites recognized by EcoRI, BamHI and ClaI which generate termini complementary to those of a variety of enzymes (e.g., EcoRI, MboI, TaqI, and HpaII), in addition to their own. A set of three of these vectors was made to accommodate all three translational reading frames. In combination, the features of these vectors afford useful advantages over expression vectors previously described, especially for the application of shot-gun cloning of genomic DNA to generate expression libraries.

Cell Division↗

PubMed1996

Healing from incest: resurrecting the buried self.

Writers on the incest experience estimate conservatively that 10% to 30% of all girls and 30% of all boys have had at least one childhood experience of incest. Incest is emotionally devastating to a child as it involves betrayal, and the irretrievable loss of trust in the adults in the child's life. Little is written about the healing processes of incest survivors. The purpose of this study was to generate a substantive grounded theory that provides an explanatory schema for understanding the healing process of adult female incest survivors. The sample consisted of 10 adult women who had a history of incest and who volunteered to participate in in-depth interviews. Data were analyzed using grounded theory techniques. Data analysis revealed that these women had buried an integral part of the self because of the trauma of incest; The healing process required resurrecting the buried self through a series of seven phases. The model generated from this research provides a heuristic for nurse therapists that assists in assessing and counseling incest survivors.

Adaptation, Psychological↗

PubMed2004

Nucleophilic participation in the transition state for human thymidine phosphorylase.

Recombinant human thymidine phosphorylase catalyzes the reaction of arsenate with thymidine to form thymine and 2-deoxyribose 1-arsenate, which rapidly decomposes to 2-deoxyribose and inorganic arsenate. The transition-state structure of this reaction was determined using kinetic isotope effect analysis followed by computer modeling. Experimental kinetic isotope effects were determined at physiological pH and 37 degrees C. The extent of forward commitment to catalysis was determined by pulse-chase experiments to be 0.70%. The intrinsic kinetic isotope effects for [1'-(3)H]-, [2'R-(3)H]-, [2'S-(3)H]-, [4'-(3)H]-, [5'-(3)H]-, [1'-(14)C]-, and [1-(15)N]-thymidines were determined to be 0.989 +/- 0.002, 0.974 +/- 0.002, 1.036 +/- 0.002, 1.020 +/- 0.003, 1.061 +/- 0.003, 1.139 +/- 0.005, and 1.022 +/- 0.005, respectively. A computer-generated model, based on density functional electronic structure calculations, was fit to the experimental isotope effect. The structure of the transition state confirms that human thymidine phosphorylase proceeds through an S(N)2-like transition state with bond orders of 0.50 to the thymine leaving group and 0.33 to the attacking oxygen nucleophile. The reaction differs from the dissociative transition states previously reported for N-ribosyl transferases and is the first demonstration of a nucleophilic transition state for an N-ribosyl transferase. The large primary (14)C isotope effect of 1.139 can occur only in nucleophilic displacements and is the largest (14)C primary isotope effect reported for an enzymatic reaction. A transition state structure with substantial bond order to the attacking nucleophile and leaving group is confirmed by the slightly inverse 1'-(3)H isotope effect, demonstrating that the transition state is compressed by the impinging steric bulk of the nucleophile and leaving group.

Catalysis↗

PubMed2004

The modelling of positron emitter production and PET imaging during carbon ion therapy.

At the carbon ion therapy facility of GSI Darmstadt in-beam positron emission tomography (PET) is used for imaging the beta+-activity distributions which are produced via nuclear fragmentation reactions between the carbon ions and the atomic nuclei of the irradiated tissue. On the basis of these PET images the quality of the irradiation, i.e. the position of the field, the particle range in vivo and even local deviations between the planned and the applied dose distribution, can be evaluated. However, for such an evaluation the measured beta+-activity distributions have to be compared with those predicted from the treatment plan. The predictions are calculated as follows: a Monte Carlo event generator produces list mode data files of the same format as the PET scanner in order to be processed like the measured ones for tomographic reconstruction. The event generator models the whole chain from the interaction of the projectiles with the target, i.e. their stopping and nuclear reactions, the production and the decay of positron emitters, the motion of the positrons as well as the propagation and the detection of the annihilation photons. The steps of the modelling, the experimental validation and clinical implementation are presented.

Carbon↗

PubMed2002

Three-dimensional common-feature hypotheses of inhibitors of calling behaviour and in vitro [14C]acetate incorporation by pheromone glands of Plodia interpunctella.

Some octopamine (OA) agonists were found to suppress the calling behaviour and pheromone biosynthesis in vitro of the Indian meal moth, Plodia interpunctella (Hübner), a stored-product pest. Compounds were screened using a calling behaviour bioassay of female P interpunctella. Three active derivatives, with activity at the nanomolar level, were identified. In order of decreasing pheromonostatic activity these were: 2-(2-ethyl-6-methylanilino)oxazolidine > 2-(2,6-diethylanilino)thiazolidine > 2-(2,6-diethylanilino)oxazolidine. These compounds showed also in vitro inhibitory activities in de novo pheromone biosynthesis. Three-dimensional pharmacophore hypotheses were built from a set of 19 compounds. Among the ten common-featured models generated by the program Catalyst/HipHop, a hypothesis including a ring aromatic group (RA), a positive ionizable group (PI) and two hydrophobic aliphatic (HpA1) features was considered to be essential for inhibitory activity in the calling behaviour and pheromone biosynthesis in vitro. Active compounds mapped well onto all the RA, PI and HpA1 features of the hypothesis. Less-active compounds were shown not to achieve the energetically favourable conformation which was found in the active molecules in order to fit the 3-D common-feature pharmacophore models. The present studies demonstrate that inhibition of calling behaviour and PBAN-stimulated incorporation of radioactivity is by OA-agonistic activity.

Acetates↗

PubMed2003

Inhibitors of calling behavior of Plodia interpunctella.

Some octopamine agonists were found to suppress the calling behavior of the stored product Indian meal moth, Plodia interpunctella. Compounds were screened using a calling behavior bioassay using female P. interpunctella. Four active derivatives, with inhibitory activity at the nanomolar range, were identified in order of decreasing activity: 2-(1-phenylethylamino)-2-oxazoline > 2-(2-ethyl,6-methylanilino)oxazolidine > 2-(2-methyl benzylamino)-2-thiazoline > 2-(2,6-diethylanilino)thiazolidine. Three-dimensional pharmacophore hypotheses were built from a set of 15 compounds. Among the ten common-featured models generated by the program Catalyst/HipHop, a hypothesis including a hydrogen-bond acceptor lipid, a hydrophobic aromatic and two hydrophobic aliphatic features was considered to be essential for inhibitory activity in the calling behavior. Active compounds mapped well onto all the hydrogen-bond acceptor lipid, hydrophobic aromatic and hydrophobic aliphatic features of the hypothesis. On the other hand, less active compounds were shown not to achieve the energetically favorable conformation that is found in the active molecules in order to fit the 3D common-feature pharmacophore models. The present studies demonstrate that inhibition of calling behavior is via an octopamine receptor.

Adrenergic alpha-Agonists↗