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PubMed1994

Inhibitors of serotonin synthesis and antagonists of serotonin 1A receptors inhibit T lymphocyte function in vitro and cell-mediated immunity in vivo.

The serotonin (5HT1A) receptor subtype is one member of the 5HT1 receptor family and is constitutively expressed on Jurkat cells and is elevated on human T lymphocytes after mitogenic activation. Published reports show that human T lymphocytes and monocytes also release 5HT after stimulation with PHA or IFN-gamma. In lymphocytes and the central nervous system, the 5HT1A receptor is coupled to regulation of adenylate cyclase. The 5HT1A receptor agonists inhibit activation of adenylate cyclase. The purpose of the experiments reported here was to investigate further the role 5HT and the 5HT1A receptor may play in the regulation of human and murine T cell activity. For this purpose, human PBMC or murine spleen cells were used for experimental purposes rather than Jurkat cells. The results show that inhibition of 5HT synthesis inhibits IL-2-stimulated human T cell proliferation and that addition of 5-hydroxytryptophan, a precursor of 5HT, reverses inhibition of T cell proliferation. The 5HT1 receptor antagonist, metitepine, and the 5HT1A selective antagonist, pindobind-5HT1A, also block T cell proliferation. Inhibition by metitepine is reversed by 5HT and by the selective 5HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino) (8-OH-DPAT). Selective 5HT1A receptor antagonists cause elevation of cAMP in human T cells. In a murine model, selective 5HT1A receptor antagonists inhibit contact sensitivity responses but not Ab responses to oxazalone in vivo. Inhibition is reversed by 8-OH-DPAT. In addition, production of Th1 cytokines, such as IL-2 and IFN-gamma, by Ag-stimulated, immune murine spleen cells is inhibited by 5HT1A receptor antagonists in vitro but not by 5HT1C/2 receptor antagonists.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1996

NMDA-dependent modulation of CA1 local circuit inhibition.

Whole-cell and extracellular recording techniques were used to examine local circuit inhibition in the CA1 region of the rat hippocampus in vitro. Activation, primarily of the recurrent inhibitory circuit by alvear stimulation, elicited an IPSP in pyramidal neurons that was dependent, in part, on NMDA receptor activation. Application of a tetanizing stimulus to the alveus evoked long-term potentiation (LTP) of the intracellularly recorded recurrent IPSPs. This LTP also was NMDA-dependent and was more sensitive to blockade by the NMDA antagonists 2-amino-5-phosphonovalerate (APV) and N-acetyl-aspartyl-glutamate, than the excitatory LTP produced by Schaffer collateral stimulation. With regard to APV, the sensitivity of inhibitory LTP was an order of magnitude greater. A biophysical simulation of hippocampal CA1 circuitry was used in a model of learned pattern recognition that included LTP in both excitatory and inhibitory recurrent circuits. In this model, selective blockade of inhibitory LTP produced aberrant spread of lateral excitation, resulting in confusion of normally distinguishable patterns of neuronal activity. Consideration is given to the possibility that selective disruption of NMDA-dependent modulation of local circuit inhibition may serve as a model for some aspects of dysfunction associated with NMDA-antagonist exposure and schizophrenia.

2-Amino-5-phosphonovalerate↗
PubMed2004

Genetic correlates of efavirenz hypersusceptibility.

BACKGROUND: Non-nucleoside reverse transcriptase inhibitor (NNRTI) hypersusceptibility is seen in approximately 30% of HIV isolates with nucleoside reverse transcriptase inhibitor (NRTI) resistance. NNRTI hypersusceptibility has been associated with improved outcomes to NNRTI-based therapy. OBJECTIVE: To determine the genetic correlates of efavirenz hypersusceptibility. METHODS: Paired baseline genotypes and phenotypes were obtained from 444 NRTI-experienced, NNRTI-naive patients. Fisher's exact tests, recursive partitioning (classification and regression trees; CART), and stepwise binary regression were used to identify specific reverse transcriptase (RT) mutations associated with efavirenz hypersusceptibility. RESULTS: In univariate analyses, 26 RT codons were associated with efavirenz hypersusceptibility (P < 0.05), the top five were 215 > 41 > 210 > 118 > 208 (all P < 0.000001). From stepwise model selection, the 215, 208 and 118 mutations remained independently predictive of efavirenz hypersusceptibility. A final binary regression model to predict efavirenz hypersusceptibility included one covariate for the 215 mutation (relative risk 2.6, P < 0.0001) and a second covariate representing either the 208 or 118 mutation (relative risk 1.8, P < 0.0001). Similarly, in a CART analysis, a mutation at codon 215 was the first split selected, followed by mutations at 208 and 118. An efavirenz hypersusceptibility genotypic score using the three mutations 208, 118 and 215 was as accurate at predicting efavirenz hypersusceptibility as a more complex scoring system using 26 mutations. CONCLUSION: Mutations at 215, 208 and 118 were independently associated with NNRTI hypersusceptibility. After confirmatory studies using other large datasets, incorporating a hypersusceptibility score into genotype interpretation algorithms will improve the prediction of NNRTI hypersusceptibility.

Alkynes↗
PubMed1980

Analysis of some two-locus systems for traits exhibiting continuous variation.

Some generalized two-locus, major-gene models for traits exhibiting continuous expression are investigated. Conditions of gametic equilibria are stated as functions of the parameters characterizing the within phenotypic-genotypic distributions. Selection is stabilizing in favor of an optimum phenotype. It is established that an increase in the phenotypic variance facilitates stability of a central polymorphic state with tighter linkage. Also, with increased phenotypic variance in an additive two-locus selection model, a HARDY-WEINBERG type of equilibrium will be less central. The rate of convergence, in this case, is slowed down with an augmented environmental background.

Genetic Linkage↗
PubMed1992

Embryonic palatal responses to teratogens in serum-free organ culture.

This study examines development of rat, mouse, and human embryonic palates in submerged, serum-free organ culture. The concentration-response profiles for retinoic acid (RA), triamcinolone (TRI), hydrocortisone (HC), dexamethasone (DEX), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were examined and the mechanisms of clefting in vitro were compared to observed in vivo responses. Craniofacial regions were dissected on gestational day (GD) 12 for mice and GD 14 for rat, and cultured for 3-4 days in Bigger's BGJb medium in flasks flushed with 50% O2, 45% N2, 5% CO2. Growth and fusion of secondary palates were scored under a dissecting microscope. In serum-free control medium, mouse and rat palatal fusion occurred within the 4-day culture period. Supplementing with fetal bovine serum (FBS) in excess of 1% interfered with growth and fusion in control medium. RA significantly inhibited fusion of mouse and rat palates at 5 x 10(-9) and 1 x 10(-10) M, respectively, with RA-induced clefting related to abnormal proliferation and differentiation of medial epithelia. In contrast, glucocorticoid-induced clefting was due to concentration-dependent inhibition of shelf growth. TRI significantly inhibited fusion at 4 x 10(-5) M, and 1 x 10(-4) M DEX or HC, inhibited fusion of 19 and 42% of shelves, respectively. The response rate for DEX in the presence of 1% FBS was increased (42% unfused). TCDD clefting was due to altered medial epithelial differentiation and 1 x 10(-8) M TCDD affected 36% of CD-1 mouse, 23% of C57BL/6N mouse, and 47% of F344 rat palates. When the medium was supplemented with 1% FBS, selenium, transferrin, and additional glutamine, the response of C57BL/6N embryos increased to 75%. This rate is similar to that reported for Trowell's-type cultures with IMEM:F12 medium and 1% FBS. The increased responsiveness to DEX or TCDD in the presence of serum suggests that an unknown factor in serum may be required for full activity. Three human embryonic palatal explants (GD 52 or 53) were cultured for 3-6 days and fused during culture. The present study demonstrates that serum-free organ culture supports development of mouse, rat, and human palatal explants. The present study demonstrates the capacity of this organ culture system to model palatogenesis for several species, and to distinguish between various mechanisms of clefting as presented through selected model compounds. This model should be useful for exploring mechanisms of activity at a cellular and molecular level.

Abnormalities, Drug-Induced↗
PubMed2003

FAST-Modelfree: a program for rapid automated analysis of solution NMR spin-relaxation data.

Herein we describe the program FAST-Modelfree for the fully automated, high throughput analysis of NMR spin-relaxation data. This program interfaces with the program Modelfree 4.1 and provides an intuitive graphical user interface for configuration as well as complete standalone operation during the model selection and rotational diffusion parameter optimization processes. FAST-Modelfree is also capable of iteratively assigning models to each spin and optimizing the parameters that describe the diffusion tensor. Tests with the protein Ribonuclease A indicate that using this iterative approach even poor initial estimates of the diffusion tensor parameters will converge to the optimal value within a few iterations. In addition to improving the quality of the final fit, this represents a substantial timesaving compared to manual data analysis and minimizes the chance of human error. It is anticipated that this program will be particularly useful for the analysis and comparison of data collected under different conditions such as multiple temperatures and the presence and absence of ligands. Further, this program is intended to establish a more uniform protocol for NMR spin-relaxation data analysis, facilitating the comparison of results both between and within research laboratories. Results obtained with FAST-Modelfree are compared with previous literature results for the proteins Ribonuclease H, E. coli glutaredoxin-1 and the Ca(2+)-binding protein S100B. These proteins represent data sets collected at both single and multiple static magnetic fields and which required analysis with both isotropic and axially symmetric rotational diffusion tensors. In all cases results obtained with FAST-Modelfree compared favorably with the original literature results.

Animals↗
PubMed2003

Enhancing radiotherapy with cyclooxygenase-2 enzyme inhibitors: a rational advance?

Results of preclinical studies suggesting that the efficacy of molecular therapies is enhanced when they are combined with radiation have generated a surge of clinical trials combining these modalities. We reviewed the literature to identify the rationale and experimental foundation supporting the use of cyclooxygenase-2 (COX-2) inhibitors with standard radiotherapy regimens in current clinical trials. Radiation affects the ability of cells to divide and proliferate and induces the expression of genes involved in signaling pathways that promote cell survival or trigger cell death. Future advances in radiotherapy will hinge on understanding mechanisms by which radiation-induced transcription of genes governs cell death and survival, the selective control of this process, and the optimal approaches to combining this knowledge with existing therapeutic modalities. COX-2 is expressed in all stages of cancer, and in several cancers its overexpression is associated with poor prognosis. Evidence from clinical and preclinical studies indicates that COX-2-derived prostaglandins participate in carcinogenesis, inflammation, immune response suppression, apoptosis inhibition, angiogenesis, and tumor cell invasion and metastasis. Clinical trial results have demonstrated that selective inhibition of COX-2 can alter the development and the progression of cancer. In animal models, selective inhibition of COX-2 activity is associated with the enhanced radiation sensitivity of tumors without appreciably increasing the effects of radiation on normal tissue, and preclinical evidence suggests that the principal mechanism of radiation potentiation through selective COX-2 inhibition is the direct increase in cellular radiation sensitivity and the direct inhibition of tumor neovascularization. Results of current early-phase studies of non-small-cell lung, esophageal, cervical, and brain cancers will determine whether therapies that combine COX-2 inhibitors and radiation will enter randomized clinical trials.

Animals↗
PubMed1981

Forecasting Australian marriage rates.

"The paper discusses the problem of modelling demographic variables for the purpose of forecasting. Two empirical model selection procedures are applied to suggest final form forecasting equations for Australian marriage rates. The suggested models are then assessed by comparing their post-sample forecast performance with that of univariate ARMA-type models of marriage rates which are regarded as approximations to marriage rate final equation models. In this instance the ARMA models are preferred for forecasting purposes. The properties of the ARMA model forecasts are then examined and the modelling strategy is contrasted with the regression method used by Withers."

Australia↗
PubMed2006

Stochastic search gene suggestion: a Bayesian hierarchical model for gene mapping.

Mapping the genes for a complex disease, such as diabetes or rheumatoid arthritis (RA), involves finding multiple genetic loci that may contribute to the onset of the disease. Pairwise testing of the loci leads to the problem of multiple testing. Looking at haplotypes, or linear sets of loci, avoids multiple tests but results in a contingency table with sparse counts, especially when using marker loci with multiple alleles. We propose a hierarchical Bayesian model for case-parent triad data that uses a conditional logistic regression likelihood to model the probability of transmission to a diseased child. We define hierarchical prior distributions on the allele main effects to model the genetic dependencies present in the human leukocyte antigen (HLA) region of chromosome 6. First, we add a hierarchical level for model selection that accounts for both locus and allele selection. This allows us to cast the problem of identifying genetic loci relevant to the disease into a problem of Bayesian variable selection. Second, we attempt to include linkage disequilibrium as a covariance structure in the prior for model coefficients. We evaluate the performance of the procedure with some simulated examples and then apply our procedure to identifying genetic markers in the HLA region that influence risk for RA. Our software is available on the website http://www.epigenetic.org/Linkage/ssgs-public/.

Alleles↗
PubMed2004

A point process framework for relating neural spiking activity to spiking history, neural ensemble, and extrinsic covariate effects.

Multiple factors simultaneously affect the spiking activity of individual neurons. Determining the effects and relative importance of these factors is a challenging problem in neurophysiology. We propose a statistical framework based on the point process likelihood function to relate a neuron's spiking probability to three typical covariates: the neuron's own spiking history, concurrent ensemble activity, and extrinsic covariates such as stimuli or behavior. The framework uses parametric models of the conditional intensity function to define a neuron's spiking probability in terms of the covariates. The discrete time likelihood function for point processes is used to carry out model fitting and model analysis. We show that, by modeling the logarithm of the conditional intensity function as a linear combination of functions of the covariates, the discrete time point process likelihood function is readily analyzed in the generalized linear model (GLM) framework. We illustrate our approach for both GLM and non-GLM likelihood functions using simulated data and multivariate single-unit activity data simultaneously recorded from the motor cortex of a monkey performing a visuomotor pursuit-tracking task. The point process framework provides a flexible, computationally efficient approach for maximum likelihood estimation, goodness-of-fit assessment, residual analysis, model selection, and neural decoding. The framework thus allows for the formulation and analysis of point process models of neural spiking activity that readily capture the simultaneous effects of multiple covariates and enables the assessment of their relative importance.

Action Potentials↗
PubMed2004

Stability-based validation of clustering solutions.

Data clustering describes a set of frequently employed techniques in exploratory data analysis to extract "natural" group structure in data. Such groupings need to be validated to separate the signal in the data from spurious structure. In this context, finding an appropriate number of clusters is a particularly important model selection question. We introduce a measure of cluster stability to assess the validity of a cluster model. This stability measure quantifies the reproducibility of clustering solutions on a second sample, and it can be interpreted as a classification risk with regard to class labels produced by a clustering algorithm. The preferred number of clusters is determined by minimizing this classification risk as a function of the number of clusters. Convincing results are achieved on simulated as well as gene expression data sets. Comparisons to other methods demonstrate the competitive performance of our method and its suitability as a general validation tool for clustering solutions in real-world problems.

Algorithms↗
PubMed1991

Patterns of change in weight/stature2 from 2 to 18 years: findings from long-term serial data for children in the Fels longitudinal growth study.

Serial weight/stature2 (W/S2) data recorded semi-annually from 2 to 18 years in the Fels longitudinal study were analyzed to establish an approach for the investigation of long-term serial changes in body fatness during childhood and adolescence in individuals. To describe patterns of change in body fatness during childhood and adolescence, a family of mathematical models was fitted to individual serial W/S2 data recorded from 250 boys and 246 girls. The selected models fitted the W/S2 data well as judged by the root mean square errors. Based on the fitted models, variables representing patterns of change in an individual were derived. These included estimated value of W/S2 at 2 years of age (W/S(2)2yr), minimum value of W/S2 (W/S2min), age at minimum value of W/S2 (Amin), maximum velocity of W/S (Vmax), age at maximum velocity of W/S2 (AVmax), maximum value of W/S2 (W/S2max), and age at maximum value of W/S2 (Amax). There were highly significant correlations between observed W/S2 at 18 years and all the derived variables except AVmax indicating, for example, that in both sexes about 25 percent of the variation in W/S2 at 18 years could be explained by when Amin occurs or by the value of W/S2min. The negative correlations (r = -0.5) between Amin and W/S2 at 18 years suggested that the earlier children reach their nadir in W/S2, the earlier they began to increase in adiposity and the fatter they were at 18 years. Likewise, the positive correlations (r approximately 0.3 and 0.5, respectively) between the W/S(2)2yr or W/S2min and W/S2 at 18 years indicated that increased childhood adiposity may lead to increased adult adiposity.

Adipose Tissue↗
PubMed1982

Moments of transfer of stimulus control in practical assembly tasks by mentally retarded adults.

Twenty vocational rehabilitation clients, divided into two aptitude groups, were trained to assemble three different 10-part apparatuses (lawn mower engine, electric drill, and bicycle brake) using three progressive prompt delay intervals (1, 3, and 5 seconds). The experimenter modeled selection and placement of each part on Trial 1 (0-second delay). On Trial 2, the modeling prompt was delayed 1, 3, or 5 seconds. On subsequent trials, a correct response increased the delay interval while an incorrect response shortened the delay interval. The 1-second delay condition produced fewest errors, most trials with no errors, and earliest acquisition. The patterns of the "moments of transfer" (shift from prompt dependent to independent responding) were similar for the high- and low-aptitude groups.

Adolescent↗
PubMed2000

A model for the evolution of high frequencies of males in an androdioecious plant based on a cross-compatibility advantage of males.

Lloyd's (1975) and Charlesworth & Charlesworth's (1978) phenotypic selection models for the maintenance of androdioecy predict that males (female-sterile individuals) must have an advantage in fertility (K) of at least two in order to invade a hermaphroditic population, and that their equilibrium frequency (x(eq)=(K - 2)/2(K - 1)) is always less than 0.5. In this paper, we develop a model in which male fertility is frequency-dependent, a situation not investigated in the previous models, to explore the conditions under which a high frequency of males (i.e. more than 50%) could be maintained at equilibrium. We demonstrate that a gametophytic self-incompatibility (GSI) locus linked to a nuclear sex determination locus can favour rare alleles through male function, by causing frequency-dependent selection. Thus, the spread of a female-sterility allele in a hermaphroditic population may be induced. In contrast with the previous models, our model can explain male frequencies greater than 50% in a functionally androdioecious species, as long as there is (i) dominance of female-sterility at the sex locus, and (ii) a few alleles at the self-incompatibility locus, even if the advantage in fertility of male phenotype is lower than two.

Biological Evolution↗
PubMed2005

Recombination shapes the natural population structure of the hyperthermophilic archaeon Sulfolobus islandicus.

Although microorganisms make up the preponderance of the biodiversity on Earth, the ecological and evolutionary factors that structure microbial populations are not well understood. We investigated the genetic structure of a thermoacidophilic crenarchaeal species, Sulfolobus islandicus, using multilocus sequence analysis of six variable protein-coding loci on a set of 60 isolates from the Mutnovsky region of Kamchatka, Russia. We demonstrate significant incongruence among gene genealogies and a lack of association between alleles consistent with recombination rates greater than the rate of mutation. The observation of high relative rates of recombination suggests that the structure of this natural population does not fit the periodic selection model often used to describe populations of asexual microorganisms. We propose instead that frequent recombination among closely related individuals prevents periodic selection from purging diversity and provides a fundamental cohesive mechanism within this and perhaps other archaeal species.

Ecosystem↗
PubMed1977

Selection and mutation at an X-linked locus.

The most general mutation-selection model with discrete non-overlapping generations is formulated for a multiallelic X-linked locus. The difference equations for the gene frequencies, though dependent on the female genotypic proportions, are shown to have a simple form. If mating is random and the rates at which various unions produce females may be expressed as products of factors depending on the male and female parental genotypes, then the female zygotic frequencies are proved to be generalized Hardy-Weinberg proportions with respect to the male and female gametic frequencies. As the main application of the formalism, assuming only that mutation is much weaker than selection, the total frequencies of mutant alleles in males and females at equilibrium are related to the mutation rates and mean selection coefficients in the two sexes.

Alleles↗
PubMed2004

[Investigation and application of gasoline sample identity technique].

Chemometrics method was used to solve the problem of automatic selecting model for the detailed hydrocarbon analysis (DHA) of gasoline samples by gas chromatography/ flame ionization detection (GC/FID). The 29 peaks in GC/FID DHA chromatogram and their amounts were selected as the discriminating parameters to establish the five pattern models for different gasoline samples, such as fluid catalytic cracking (FCC) gasoline, coking gasoline, straight run gasoline, reformed gasoline, and alkylation gasoline. The principle component analysis (PCA) and Soft Independent Modeling of Class Analogies (SIMCA) were used to classify the gasoline samples and to identify the unknown samples according to the above pattern models. One hundred gasoline samples, derived from known resources, were employed to validate the reliability of the sample identity technique. With the help of the pattern identity method referred here, the automation of GC/FID DHA method becomes possible.

Chromatography, Gas↗
PubMedDate not supplied

Comparison of consensus scoring strategies for evaluating computational models of protein-ligand complexes.

Here, the comparisons of performance of nine consensus scoring strategies, in which multiple scoring functions were used simultaneously to evaluate candidate structures for a protein-ligand complex, in combination with nine scoring functions (FlexX score, GOLD score, PMF score, DOCK score, ChemScore, DrugScore, PLP, ScreenScore, and X-Score), were carried out. The systematic naming of consensus scoring strategies was also proposed. Our results demonstrate that choosing the most appropriate type of consensus score is essential for model selection in computational docking; although the vote-by-number strategy was an effective selection method, the number-by-number and rank-by-number strategies were more appropriate when computational tractability was taken into account. By incorporating these consensus scores into the FlexX program, reasonable complex models can be obtained more efficiently than those selected by independent FlexX scores. These strategies might also improve the scoring of other docking programs, and more-effective structure-based drug design should result from these improvements.

Computer Simulation↗