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PubMed1986

Modelling study of spinal generators structure; the role of alpha motoneurons, Renshaw cells and Ia interneurons in locomotion.

The properties of a model system composed of nets of motoneurons, Ia interneurons and Renshaw cells corresponding to the set of muscles driving one joint were analyzed from the point of view of their participation in locomotion control, i.e., generation of signals driving individual muscles. The model was constructed of neuron-like analog elements. The relations between the structure of the system, its control by tonic and phasic inputs and the properties of the generated signals were examined. The pattern of activity of motoneuron-like elements was considered to reflect the physiological pattern of muscle activity during locomotion. The network modelled in this way was an adjustable system, i.e., the parameters of the generated pattern could be varied by both tonic and phasic signals. A phasic signal acting on a background of moderate tonic signals seemed to enable a broader adjustment of the parameters of the generated pattern than tonic signals only. The best correspondence between generated and physiological patterns was obtained when the Renshaw cells were additionally and selectively inhibited by tonic signals.

Animals↗
PubMed2006

Synergistic pathogenic effects of combined mouse monoclonal anti-desmoglein 3 IgG antibodies on pemphigus vulgaris blister formation.

Pemphigus vulgaris (PV) is an autoimmune blistering disease caused by anti-desmoglein 3 (Dsg3) IgG antibodies. Previously, we generated an active mouse model for PV by adoptive transfer of splenocytes from immunized or naive Dsg3(-/-) mice. In this study, we isolated 10 anti-Dsg3 IgG mAbs (NAK-series) from PV model mice generated by transfer of naive Dsg3(-/-) splenocytes. We characterized their epitopes using domain-swapped and point-mutated Dsg1/Dsg3 molecules and examined their pathogenic activities in blister formation in three different assays. In a passive transfer model using neonatal mice, eight of 10 NAK mAbs showed pathogenic activity when injected together with half the minimum pathogenic dose of anti-Dsg1 IgG autoantibodies from pemphigus foliaceus (PF) patients. None of the mAbs could induce the PV phenotype when individual hybridoma clones were inoculated by peritoneal injection into adult Rag2(-/-) mice. NAK mAbs displayed a range of potency in an in vitro dissociation assay using primary cultured mouse keratinocytes. Interestingly, when multiple hybridoma clones recognizing different epitopes were inoculated in combination, recipient mice developed the PV phenotype. In vitro dissociation assays confirmed that combined NAK mAbs had synergistic pathogenic effects. These findings indicate that although an individual anti-Dsg3 IgG is not sufficient to cause blistering in adult mice, several together can induce the PV phenotype. These mAbs will provide a valuable tool to investigate the molecular mechanisms of blister formation, mimicking the effects of the polyclonal IgG antibodies found in patients.

Aging↗
PubMed2001

Using decision tree induction to model oculomotor data.

Decision tree induction is a machine learning method used to generate classification models from data sets. Numerous decision trees were constructed to examine relationships between oculomotor test parameters and lesion sites in a data set containing cases with operated cerebello-pontine angle tumour, operated hemangioblastoma, infarction of cerebello-brainstem and Ménière's disease, and control subjects. The aim was to find useful parameter combinations with discriminatory power. Decision trees constructed using both pursuit eye movements and saccadic eye movements yielded the best classification results. This is reasonable: oculomotor test results vary according to the site of the lesion and so the performance ability of subjects has to be taken into account in the classification. The decision tree program was able to generate classification models from the oculomotor data set. Generated decision trees were intelligible and can be utilized in physicians' research work.

Decision Making↗
PubMed2004

Intrusion detection using rough set classification.

Recently machine learning-based intrusion detection approaches have been subjected to extensive researches because they can detect both misuse and anomaly. In this paper, rough set classification (RSC), a modern learning algorithm, is used to rank the features extracted for detecting intrusions and generate intrusion detection models. Feature ranking is a very critical step when building the model. RSC performs feature ranking before generating rules, and converts the feature ranking to minimal hitting set problem addressed by using genetic algorithm (GA). This is done in classical approaches using Support Vector Machine (SVM) by executing many iterations, each of which removes one useless feature. Compared with those methods, our method can avoid many iterations. In addition, a hybrid genetic algorithm is proposed to increase the convergence speed and decrease the training time of RSC. The models generated by RSC take the form of "IF-THEN" rules, which have the advantage of explication. Tests and comparison of RSC with SVM on DARPA benchmark data showed that for Probe and DoS attacks both RSC and SVM yielded highly accurate results (greater than 99% accuracy on testing set).

Algorithms↗
PubMed1987

The influence of dose and dose rate of total lymphoid irradiation in the rat cardiac allograft model.

Immunosuppression generated by total lymphoid irradiation (TLI) may be of use in solid organ transplantation. We have investigated the use of TLI in the rat cardiac allograft model. Lewis rats received TLI from a cobalt-60 machine. The daily dose was 1.25 Gy and treatments were administered 4 days per week. We performed experiments to assess the effect of dose rate upon graft survival. The dose rate was varied by changing the source to animal distance and by using a lead attenuator. Cardiac allografts from each ACI donor rat were transplanted to the recipient Lewis rat's abdomen utilizing microvascular surgical technique. Heart graft survival times (GST) were monitored by direct palpation of the cardiac impulse. Immune function was measured by an activity index of the mixed lymphocyte reaction. In the absence of any immunosuppression there was a mean GST of 6.9 +/- 0.3 days. When a graft was placed the day following completion of TLI, there was an increase in GST as the total TLI dose was increased. Mean GST (+/- S.E.) following 5, 10, and 15 Gy were 12.3 +/- 1.3, 14.5 +/- 1.3, and 25.5 +/- 1.1 days, respectively. Following 20 Gy, GST decreased because of irradiation induced pulmonary toxicity and host death. When 3.5 weeks were allowed to elapse between the completion of TLI and transplantation, GST were less than those seen with equivalent doses of TLI and early transplantation. Mean GST following 5, 10, and 15 Gy and a delayed transplant were 7.2 +/- 0.1, 10.7 +/- 1.2, and 19.0 +/- 3.5 days, respectively. We tested the effect of dose rate upon GST.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

Can virtual reality improve anatomy education? A randomised controlled study of a computer-generated three-dimensional anatomical ear model.

INTRODUCTION: The use of computer-generated 3-dimensional (3-D) anatomical models to teach anatomy has proliferated. However, there is little evidence that these models are educationally effective. The purpose of this study was to test the educational effectiveness of a computer-generated 3-D model of the middle and inner ear. METHODS: We reconstructed a fully interactive model of the middle and inner ear from a magnetic resonance imaging scan of a human cadaver ear. To test the model's educational usefulness, we conducted a randomised controlled study in which 28 medical students completed a Web-based tutorial on ear anatomy that included the interactive model, while a control group of 29 students took the tutorial without exposure to the model. At the end of the tutorials, both groups were asked a series of 15 quiz questions to evaluate their knowledge of 3-D relationships within the ear. RESULTS: The intervention group's mean score on the quiz was 83%, while that of the control group was 65%. This difference in means was highly significant (P < 0.001). DISCUSSION: Our findings stand in contrast to the handful of previous randomised controlled trials that evaluated the effects of computer-generated 3-D anatomical models on learning. The equivocal and negative results of these previous studies may be due to the limitations of these studies (such as small sample size) as well as the limitations of the models that were studied (such as a lack of full interactivity). Given our positive results, we believe that further research is warranted concerning the educational effectiveness of computer-generated anatomical models.

Anatomy↗
PubMed2006

Modeling the pore structure of voltage-gated sodium channels in closed, open, and fast-inactivated conformation reveals details of site 1 toxin and local anesthetic binding.

In this work molecular modeling was applied to generate homology models of the pore region of the Na(v)1.2 and Na(v)1.8 isoforms of human voltage-gated sodium channels. The models represent the channels in the resting, open, and fast-inactivated states. The transmembrane portions of the channels were based on the equivalent domains of the closed and open conformation potassium channels KcsA and MthK, respectively. The critical selectivity loops were modeled using a structural template identified by a novel 3D-search technique and subsequently merged with the transmembrane portions. The resulting draft models were used to study the differences of tetrodotoxin binding to the tetrodotoxin-sensitive Na(v)1.2 (EC50: 0.012 microM) and -insensitive Na(v)1.8 (EC50: 60 microM) isoforms, respectively. Furthermore, we investigated binding of the local anesthetic tetracaine to Na(v)1.8 (EC50: 12.5 microM) in resting, conducting, and fast-inactivated state. In accordance with experimental mutagenesis studies, computational docking of tetrodotoxin and tetracaine provided (1) a description of site 1 toxin and local anesthetic binding sites in voltage-gated sodium channels. (2) A rationale for site 1 toxin-sensitivity versus -insensitivity in atomic detail involving interactions of the Na(v)1.2 residues F385-I and W943-II. (3) A working hypothesis of interactions between Na(v)1.8 in different conformational states and the local anesthetic tetracaine.

Anesthetics↗
PubMed1996

Endogenous fertility and the Henry George Theorem.

"Models of endogenous demographic change deal with population size as an additional object of the welfare analysis. In these models the overlapping-generations (OLG) model serves as the basic framework. In club theory, too, population size is treated as an endogenous variable. In local public goods (LPG) models, the so-called Henry George Theorem, which requires local public expenditures to be financed by a 100% tax on aggregate land rent, is known as a (first-order) condition for club efficiency. The present paper establishes and exploits an isomorphism between steady states of the OLG model and allocations of the LPG model. The paper revisits Samuelson's fallacy concerning his goldenest golden rule and it explores institutional arrangements that sustain the optimum growth of population."

Demography↗
PubMed2004

Assessing the distinguishability of models and the informativeness of data.

A difficulty in the development and testing of psychological models is that they are typically evaluated solely on their ability to fit experimental data, with little consideration given to their ability to fit other possible data patterns. By examining how well model A fits data generated by model B, and vice versa (a technique that we call landscaping), much safer inferences can be made about the meaning of a model's fit to data. We demonstrate the landscaping technique using four models of retention and 77 historical data sets, and show how the method can be used to: (1) evaluate the distinguishability of models, (2) evaluate the informativeness of data in distinguishing between models, and (3) suggest new ways to distinguish between models. The generality of the method is demonstrated in two other research areas (information integration and categorization), and its relationship to the important notion of model complexity is discussed.

Cognition↗
PubMed2000

Modeling of integrated Lamb waves generation systems using a coupled finite element-normal modes expansion method

As part of the research work on Smart Materials and Structures, the development of self-monitoring materials is an emerging issue. In the case of plate-shaped structures, Lamb waves can be used for their relevant properties: long-range propagation, sensitivity to internal flaws and whole-thickness interrogation. This concept requires the use of thin piezoelectric transducers integrated to the structure. Since it is of primary importance to be able to control the generated modes, a suitable modeling technique of this kind of system has been tested on different cases of practical interest. The model uses a coupled finite element-normal modes expansion approach, which allows one to consider either the case of bonded or embedded transducers. The results presented deal with examples of multi-element transducers integrated to composite materials. The influence of parameters such as the dimensions, positions and relative excitation delays of the transducers is studied.

Journal Article↗
PubMed1997

Highest level automatisms in the nervous system: a theory of functional principles underlying the highest forms of brain function.

A concept that all hierarchical levels of the nervous system are built according to the same functional principles is proposed. Each level is responsible for a discrete type or set of automatisms, is a learning system, and contains two distinct functional subdivisions: (1) a controller, a subsystem providing a governing set of rules or commands-a control law-that directs the action of the recipient of these rules-the controlled object; and (2) a model, a subsystem that generates a model of object behavior, i.e. afferent information flow expected from the controlled object. A control system such as this receives two types of afferent signals-initiating and informational. The difference between these signals is that a control system minimizes initiating signals during the realization of an automatism, i.e. a control neural network utilizes informational signals to compute the proper output that minimizes the initiating input signal. A mismatch or error signal, a type of initiating signal, is responsible for learning. Both the control law and the model can be adjusted during learning. The learning process starts when the error signal increases and stops when it is minimized. A network hierarchy is structurally and functionally organized in such a way that a lower control system in the nervous system becomes the controlled object for a higher one. This hierarchy leads to a generalization of encoded functional parameters and, consequently, the working space for each higher level control system becomes more abstracted. This is the reason why each hierarchical level within the control nervous system uses detectors specific for feature of the controlled object and the environment that match the control needs in order to obtain information about the current state of the object in the environment. Movement of information toward higher hierarchical levels also is accompanied by an increase in the duration of initiating signals within each control system. The ability to store a long prehistory of preceding events is considered as the mechanism that necessitated the invention of more complex and more rapid forms of learning such as operant learning, and made possible more complex multistep computational algorithms that require memorization of the results of previous intermediate computations. The functions of the cerebellum, the limbic system and the cortico-basal ganglia-thalamocortical loops are analyzed to illustrate the utility and applicability of this theoretical concept. Basal ganglia-thalamocortical loops are described as modeling, predictive loops, and their dopaminergic innervation as an error distribution system.

Automatism↗
PubMed2002

NMR and Bayesian regularized neural network regression for impurity determination of 4-aminophenol.

A method for the determination of 4-aminophenol as an impurity in paracetamol (N-(4-hydroxyphenyl)-acetamide) by proton nuclear magnetic resonance ((1)H-NMR) spectroscopy has been developed. The (13)C-satellite from the protons in the ortho position from the hydroxyl group in paracetamol was used as an internal standard, although these peaks interfered with the peaks from the protons in 4-aminophenol. Because of interference in the spectra and non-linearity over a wide calibration range, a Bayesian regularized neural network model was used for calibration. Various kinds of data preprocessing were examined: zero filling, multiplication by a negative exponential function (line broadening), followed by Fourier transformation of the free induction decay (FID). The NMR spectral data were automatically phased and shift-adjusted by means of a genetic algorithm. Multiplicative scatter correction and data compression by wavelets and sequential zeroing of weights variable selection were performed to obtain an optimal calibration model. Neither zero filling of the FID nor line broadening improved the calibration models with regard to error of prediction, so these processes were excluded in the final model. The generated Bayesian regularized network model was evaluated with an independent test set. Four different models with different test sets were constructed to explore the quality of the calibration. The mean error of the optimal calibration model was 25.3 x 10(-6) weight of 4-aminophenol per weight paracetamol. The method is characterized by being relative fast, simple and sufficient sensitive for typical pharmaceutical impurity determinations.

Acetaminophen↗
PubMed2003

Polybrominated biphenyl exposure and benign breast disease in a cohort of US women.

PURPOSE: We examined the relation between serum polybrominated biphenyl (PBB) levels and the risk of benign breast disease in a cohort of Michigan women unintentionally exposed to PBBs in 1973 and interviewed in 1997. METHODS: We used extended Cox models to generate adjusted hazard ratios; models included polychlorinated biphenyls (PCBs) and risk factors for benign breast disease reported in the literature. RESULTS: Two hundred fourteen (23%) of 951 women reported benign breast disease diagnosed by a physician. Compared with women with low PBB exposure, benign breast disease was not reported more frequently among those with moderate (>1-12 parts per billion [ppb]), (odds ratio [OR] 1.08, 95% confidence interval [CI] = 0.80-1.45), or high (>12 ppb), (OR 0.79, 95% CI = 0.46-1.38) PBB exposure. PCB exposure was also not associated with self-reported physician-diagnosed benign breast disease. Age, smoking, and annual number of health-care provider visits were significantly associated with benign breast disease. CONCLUSIONS: Our analysis did not demonstrate an association between serum PBB level and self- reported physician-diagnosed benign breast disease. We did observe an increased risk of benign breast disease for women who smoked, an association that has not been consistently found in previous studies.

Adolescent↗
PubMed2006

Secretory phospholipase A2 from Arabidopsis thaliana: insights into the three-dimensional structure and the amino acids involved in catalysis.

A low-molecular weight phospholipase A2 from Arabidopsis thaliana, isoform phospholipase A2-alpha, has been expressed in Escherichia coli in the form of inclusion bodies, refolded, and purified to homogeneity to yield the active mature enzyme. The enzyme was characterized with respect to pH, temperature optimum, and Ca2+ ion requirement. The enzyme has been shown to be a true secretory phospholipase A2 that requires Ca2+ ions in the millimolar range and belongs to group XIB. On the basis of the three-dimensional structures of secretory phospholipase A2 forms (sPLA2s) from bee venom and bovine pancreas, a homology model was generated. Analysis of this model and alignments of different plant sPLA2s showed that the common His-Asp dyad of animal sPLA2s does not exist in plant sPLA2s. In place of the aspartate residue of the dyad, the plant enzymes of group XIA contain a histidine residue, and the enzymes of group XIB contain a serine or an asparagine residue. Mutagenesis of amino acids supposed to be involved in catalysis has shown that His62, the calcium-coordinating Asp63, and the above-mentioned Ser79 residue are essential for activity.

Amino Acid Sequence↗
PubMed2006

Genetic susceptibility to polyI:C-induced IFNalpha/beta-dependent accelerated disease in lupus-prone mice.

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology. Associations between viral infections and the onset of SLE have been suggested, and recent studies have provided evidence that type I interferons (IFNalpha/beta) might play a role in the SLE disease process. Viruses and interferons have also been implicated in mouse models of SLE. We generated a model of accelerated proteinuria, in which lupus-prone mice were injected repeatedly with polyinosinic:polycytidylic acid (polyI:C), mimicking exposure to virus-derived double stranded RNA (dsRNA), leading to the production of IFNalpha/beta. PolyI:C-treated (B6.Nba2 x NZW)F1 and (B6 x NZW)F1 hybrid mice developed significantly increased levels of anti-dsDNA autoantibodies, characteristic of lupus. Most significantly, polyI:C-treated (B6.Nba2 x NZW)F1 mice, but not (B6 x NZW)F1 or parental strains, developed lupus-like nephritis in an accelerated fashion, which was dependent on IFNalpha/beta and associated with elevated deposition of total IgG, IgG2a and complement factor C3 in the glomerular capillary walls. These data suggest that reagents, which increase the levels of endogenous IFNalpha/beta (directly or indirectly), can accelerate the course of lupus-like nephritis, the development of which is dependent on the presence of both NZW- and Nba2-encoded genes.

Animals↗
PubMed2002

Increased taxon sampling greatly reduces phylogenetic error.

Several authors have argued recently that extensive taxon sampling has a positive and important effect on the accuracy of phylogenetic estimates. However, other authors have argued that there is little benefit of extensive taxon sampling, and so phylogenetic problems can or should be reduced to a few exemplar taxa as a means of reducing the computational complexity of the phylogenetic analysis. In this paper we examined five aspects of study design that may have led to these different perspectives. First, we considered the measurement of phylogenetic error across a wide range of taxon sample sizes, and conclude that the expected error based on randomly selecting trees (which varies by taxon sample size) must be considered in evaluating error in studies of the effects of taxon sampling. Second, we addressed the scope of the phylogenetic problems defined by different samples of taxa, and argue that phylogenetic scope needs to be considered in evaluating the importance of taxon-sampling strategies. Third, we examined the claim that fast and simple tree searches are as effective as more thorough searches at finding near-optimal trees that minimize error. We show that a more complete search of tree space reduces phylogenetic error, especially as the taxon sample size increases. Fourth, we examined the effects of simple versus complex simulation models on taxonomic sampling studies. Although benefits of taxon sampling are apparent for all models, data generated under more complex models of evolution produce higher overall levels of error and show greater positive effects of increased taxon sampling. Fifth, we asked if different phylogenetic optimality criteria show different effects of taxon sampling. Although we found strong differences in effectiveness of different optimality criteria as a function of taxon sample size, increased taxon sampling improved the results from all the common optimality criteria. Nonetheless, the method that showed the lowest overall performance (minimum evolution) also showed the least improvement from increased taxon sampling. Taking each of these results into account re-enforces the conclusion that increased sampling of taxa is one of the most important ways to increase overall phylogenetic accuracy.

Likelihood Functions↗
PubMed2002

Comparative ab initio prediction of gene structures using pair HMMs.

We present a novel comparative method for the ab initio prediction of protein coding genes in eukaryotic genomes. The method simultaneously predicts the gene structures of two un-annotated input DNA sequences which are homologous to each other and retrieves the subsequences which are conserved between the two DNA sequences. It is capable of predicting partial, complete and multiple genes and can align pairs of genes which differ by events of exon-fusion or exon-splitting. The method employs a probabilistic pair hidden Markov model. We generate annotations using our model with two different algorithms: the Viterbi algorithm in its linear memory implementation and a new heuristic algorithm, called the stepping stone, for which both memory and time requirements scale linearly with the sequence length. We have implemented the model in a computer program called DOUBLESCAN. In this article, we introduce the method and confirm the validity of the approach on a test set of 80 pairs of orthologous DNA sequences from mouse and human. More information can be found at: http://www.sanger.ac.uk/Software/analysis/doublescan/

Algorithms↗
PubMed2000

Intramolecular interactions regulate SAP97 binding to GKAP.

Membrane-associated guanylate kinase homologs (MAGUKs) are multidomain proteins found to be central organizers of cellular junctions. In this study, we examined the molecular mechanisms that regulate the interaction of the MAGUK SAP97 with its GUK domain binding partner GKAP (GUK-associated protein). The GKAP-GUK interaction is regulated by a series of intramolecular interactions. Specifically, the association of the Src homology 3 (SH3) domain and sequences situated between the SH3 and GUK domains with the GUK domain was found to interfere with GKAP binding. In contrast, N-terminal sequences that precede the first PDZ domain in SAP97, facilitated GKAP binding via its association with the SH3 domain. Utilizing crystal structure data available for PDZ, SH3 and GUK domains, molecular models of SAP97 were generated. These models revealed that SAP97 can exist in a compact U-shaped conformation in which the N-terminal domain folds back and interacts with the SH3 and GUK domains. These models support the biochemical data and provide new insights into how intramolecular interactions may regulate the association of SAP97 with its binding partners.

Adaptor Proteins, Signal Transducing↗