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PubMed2004

Reconstruction of ancestral protein sequences and its applications.

BACKGROUND: Modern-day proteins were selected during long evolutionary history as descendants of ancient life forms. In silico reconstruction of such ancestral protein sequences facilitates our understanding of evolutionary processes, protein classification and biological function. Additionally, reconstructed ancestral protein sequences could serve to fill in sequence space thus aiding remote homology inference. RESULTS: We developed ANCESCON, a package for distance-based phylogenetic inference and reconstruction of ancestral protein sequences that takes into account the observed variation of evolutionary rates between positions that more precisely describes the evolution of protein families. To improve the accuracy of evolutionary distance estimation and ancestral sequence reconstruction, two approaches are proposed to estimate position-specific evolutionary rates. Comparisons show that at large evolutionary distances our method gives more accurate ancestral sequence reconstruction than PAML, PHYLIP and PAUP*. We apply the reconstructed ancestral sequences to homology inference and functional site prediction. We show that the usage of hypothetical ancestors together with the present day sequences improves profile-based sequence similarity searches; and that ancestral sequence reconstruction methods can be used to predict positions with functional specificity. CONCLUSIONS: As a computational tool to reconstruct ancestral protein sequences from a given multiple sequence alignment, ANCESCON shows high accuracy in tests and helps detection of remote homologs and prediction of functional sites. ANCESCON is freely available for non-commercial use. Pre-compiled versions for several platforms can be downloaded from ftp://iole.swmed.edu/pub/ANCESCON/.

Amino Acid Sequence↗

PubMed1999

Cross-validated factor structures and factor-based subscales for PASS and PASSING.

Program Analysis of Service Systems (PASS 3) and Program Analysis of Service Systems' Implementation of Normalization Goals (PASSING) are used internationally to assess service quality in mental retardation and other fields. In two studies, we derived and cross-validated the factor structures of these program evaluation instruments. In Study 1, based on 626 PASS 3 evaluations, four factors provided a good fit to the cross-validation data. In Study 2, based on 633 PASSING evaluations, three factors furnished a good fit to the cross-validation data. Similarities between the two factor structures, parallels with the structural and functional service dimensions emphasized in ecological approaches to evaluation, and practical uses in program evaluation of subscales based on the factors were discussed.

Chi-Square Distribution↗

PubMed2002

Genetic parameter estimation for milk yield over multiple parities and various lengths of lactation in Danish Jerseys by random regression models.

The objectives of this study were to test for heterogeneity of genetic and environmental variance among completed and extended records from different lactations or different days in milk (DIM) and to build a model that accounts for this heterogeneity. A total of 147,457 305-d milk yield records from Danish Jersey cows calving between 1984 and early 1999 from two regions of Denmark were used in this study. Results showed that DIM and parity influenced parameters estimated from an animal model with repeated records. Therefore, the data were analyzed using random-regression models that allow the covariance between measurements to change gradually with DIM and parity. Random regressions were fitted for additive genetic effects and permanent environmental effects using second- or third-order normalized Legendre polynomials for DIM and parity. Variances of random-regression coefficients associated with all orders of the polynomials were significant. Based on these parameter estimates, a covariance function (CF) was defined. The CF showed that the heritability decreases over parities, but within each parity heritability increases with DIM, whereas variance of permanent environmental effects increases over parities and decreases with DIM. Generally, genetic correlations were higher between records with similar DIM and parity. The results indicate that there are problems with the extension procedure used to predict 305-d milk yields. Using the covariance functions estimated in this study, breeding values could be predicted that take into account the covariance structure between records from different parities and different DIM.

Analysis of Variance↗

PubMed2006

Testing for crossover of two hazard functions using Gail and Simon's method.

Crossover of two hazard functions is sometimes called qualitative nonproportionality where the hazard ratio could be >1 in some time intervals but <1 in some other intervals. Investigators often wish to know whether a beneficial treatment effect exists over a long period of time (i.e., no crossover). This information is important for the management of safety and efficacy of a new treatment in long-term use. Also, if crossover occurs, the commonly used statistical methods, such as Cox proportional hazards model or linear rank tests, may not be appropriate. Graphical display may be used to visually examine whether there are crossovers in the observed hazard functions. A relevant question is whether the observed crossover of two hazard functions is due to chance variation. In this article, we propose a class of tests for crossover of two hazard functions. The study follow-up period is divided into nonoverlapping time intervals, and the weighted linear rank statistic, including logrank and generalized Wilcoxon statistics, can be calculated from each interval. These statistics are asymptotically independent and have normal distributions. Treating each interval as a "patient subset," qualitative tests of interactions between treatment and patient subsets can naturally apply. For our purpose, we consider the likelihood ratio test proposed by Gail and Simon. Two examples are used to illustrate this approach. The proposed test procedures are also studied through simulations.

Antineoplastic Agents↗

PubMed2003

A putative mitochondrial fission gene from the ectomycorrhizal ascomycete Tuber borchii Vittad.: cloning, characterisation and phylogeny.

Mitochondrial binary division is a complex process occurring in multiple steps, mediated by several proteins. In Saccharomyces cerevisiae, a mitochondrial membrane protein, Fis1p, is required for the proper assembly of the mitochondrial division apparatus. In this study, we report the cloning, characterisation and phylogenetic analysis of Tbfis1, a gene from the ectomycorrhizal ascomycetous truffle Tuber borchii, encoding for an orthologue of S. cerevisiae Fis1p. The Tbfis1 coding region consists of a 468-nucleotide open reading frame interrupted by four introns, which encodes for a polypeptide of 155 amino acids, having a predicted transmembrane domain structure typical of the Fis1p Family. Southern blot analysis revealed that Tbfis1 is a single-copy gene in the T. borchii genome. Tbfis1 is highly expressed during the first stages of T. borchii fruit body ripening, while its expression decreases during T. borchii mycelium ageing. Also, Virtual Northern blot analysis revealed Tbfis1 expression in the symbiotic phase of the fungus life cycle. Phylogenetic analysis allowed the identification of Tbfis1 orthologues in filamentous fungi, yeasts, plants, worms, flies and mammals, indicating that the function of the protein coded by this gene has been conserved during evolution.

Amino Acid Sequence↗

PubMed2002

Evolution of arginine deiminase (ADI) pathway genes.

We have analyzed the evolution of the three genes encoding structural enzymes of the arginine deiminase (ADI) pathway, arginine deiminase (ADI), ornithine transcarbamoylase (OTC), and carbamate kinase (CK) in a wide range of organisms, including Archaea, Bacteria, and Eukarya. This catabolic route was probably present in the last common ancestor to all the domains of life. The results obtained indicate that these genes have undergone a complex evolutionary history, including horizontal transfer events, duplications, and losses. Therefore, these genes are not adequate to infer organismal relationships at deep branching levels, but they provide an insight into how catabolic genes evolved and were assembled into metabolic pathways. Our results suggest that the three genes evolved independently and were later assembled into a single cluster with functional interdependence, thus, providing support for the gene recruitment hypothesis. Furthermore, the molecular phylogenetic analysis of OTC suggests a new classification of these genes into three subfamilies.

Amino Acid Sequence↗

PubMed2004

Divergence in gene expression related to variation in host specificity of an ectomycorrhizal fungus.

Ectomycorrhizae are formed by mutualistic interactions between fungi and the roots of woody plants. During symbiosis the two organisms exchange carbon and nutrients in a specific tissue that is formed at the contact between a compatible fungus and plant. There is considerable variation in the degree of host specificity among species and strains of ectomycorrhizal fungi. In this study, we have for the first time shown that this variation is associated with quantitative differences in gene expression, and with divergence in nucleotide sequences of symbiosis-regulated genes. Gene expression and sequence evolution were compared in different strains of the ectomycorrhizal fungus Paxillus involutus; the strains included Nau, which is not compatible with birch and poplar, and the two compatible strains Maj and ATCC200175. On a genomic level, Nau and Maj were very similar. The sequence identity was 98.9% in the 16 loci analysed, and only three out of 1075 genes analysed by microarray-based hybridizations had signals indicating differences in gene copy numbers. In contrast, 66 out of the 1075 genes were differentially expressed in Maj compared to Nau after contact with birch roots. Thirty-seven of these symbiosis-regulated genes were also differentially expressed in the ATCC strain. Comparative analysis of DNA sequences of the symbiosis-regulated genes in different strains showed that two of them have evolved at an enhanced rate in Nau. The sequence divergence can be explained by a decreased selection pressure, which in turn is determined by lower functional constraints on these proteins in Nau as compared to the compatible strains.

Base Sequence↗

PubMedDate not supplied

A comparison of analytical methods for the study of fractional Brownian motion.

Fractional Brownian motion (FBM) provides a useful model for many physical phenomena demonstrating long-term dependencies and l/f-type spectral behavior. In this model, only one parameter is necessary to describe the complexity of the data, H, the Hurst exponent. FBM is a nonstationary random function not well suited to traditional power spectral analysis however. In this paper we discuss alternative methods for the analysis of FBM, in the context of real-time biomedical signal processing. Regression-based methods utilizing the power spectral density (PSD), the discrete wavelet transform (DWT), and dispersive analysis (DA) are compared for estimation accuracy and precision on synthesized FBM datasets. The performance of a maximum likelihood estimator for H, theoretically the best possible estimator, are presented for reference. Of the regression-based methods, it is found that the estimates provided by the DWT method have better accuracy and precision for H > 0.5, but become biased for low values of H. The DA method is most accurate for H < 0.5 for a 256-point data window size. The PSD method was biased for both H < 0.5 and H > 0.5.

Bias↗

PubMedDate not supplied

Cervical vertebral fractures in 56 dogs: a retrospective study.

The clinicopathological features of cervical fractures in 56 dogs were reviewed. "Hit by car" (HBC) was the most common inciting cause, and the axis and atlas were the vertebrae most frequently affected. Surgical treatment was associated with high (36%) perioperative mortality. However, all dogs that survived the perioperative period achieved functional recovery. Functional recovery was achieved in 25 (89%) of 28 nonsurgically treated dogs with adequate follow-up. Overall, severity of neurological deficits (nonambulatory status) and prolonged interval (five days or longer) from trauma to referral were associated with poorer outcome. Nonsurgical treatment is a viable therapeutic approach for many dogs with cervical fractures. Early neck immobilization and prompt referral are recommended, because delay in referral decreases the likelihood of functional recovery.

Accidents, Traffic↗

PubMed2006

The relationship between viewing US-produced television programs and intentions to drink alcohol among a group of Norwegian adolescents.

The aim of this study was to examine the influence of exposure to US-produced television programs and family rules prohibiting alcohol use on the development of normative beliefs, expectancies, and intentions to drink alcohol in the next 12 months among a group of Norwegian adolescents who reported that they had not previously consumed alcohol. Data were collected via a survey administered to 622 eighth and ninth graders enrolled at ten junior highs in southeastern Norway. To examine these relationships we tested the fit of a structural equation model which was based on the Theory of Planned Behavior (Ajzen, 1988). Data from the non-drinkers (n= 392, 63% of the respondents) were used. To control for the influence of peer drinking on behavioral intentions, our model was tested under two group conditions: (1) those subjects reporting that they have no friends who drink alcohol and (2) those subjects reporting that they have one or more friends who drink. The findings indicate that the influence of TV exposure was a significant predictor (directly) of normative beliefs, expectancies (indirectly) and intentions to drink (both directly and indirectly) only for those subjects who reported having no friends who drink. For the group with non-drinking friends, family rules constrain intentions only indirectly by influencing normative beliefs. For those with friends who drink, however, family rules have a direct (inverse) effect on intentions. It is concluded that exposure to US-produced television programs functions as a limited knowledge source only for those subjects who had little or no personal experience with alcohol while the presence of family rules have limited impact on behavioral intentions.

Adolescent↗

PubMed2005

Olfactory impairments in patients with unilateral cerebellar lesions are selective to inputs from the contralesional nostril.

Functional imaging studies of olfaction have consistently reported odorant-induced activation of the cerebellum. However, the cerebellar role in olfaction remains unknown. We examined the olfactory and olfactomotor abilities of patients with unilateral cerebellar lesions, comparing performance within subjects across nostrils, as well as between subjects with age-matched and young controls. Regarding olfactory performance, initial testing revealed that patients had a contralesional impairment in olfactory identification but not olfactory detection threshold. However, when tested under conditions that prevented compensatory sniffing strategies, the patients also exhibited a contralesional olfactory detection impairment. Regarding olfactomotor function, a healthy olfactomotor system generates sniffs that are (1) sufficiently vigorous and (2) inversely proportional to odorant concentration in sniff mean airflow velocity, maximum airflow velocity, volume, and duration. Patients' sniffs were lower in overall airflow velocity and volume in comparison with control participants. Furthermore, reduced sniff velocity predicted poorer detection thresholds in patients. Finally, whereas young controls used concentration-dependent sniffs, there was a trend in that direction only for age-matched controls. Patients used sniffs that were concentration invariant. In conclusion, cerebellar lesions impacted olfactory and olfactomotor performance. These findings strongly implicate an olfactocerebellar pathway prominent in odor identification and detection that functionally connects each nostril primarily to the contralateral cerebellum.

Acoustic Stimulation↗

PubMed2001

Adaptive procedures in psychophysical research.

As research on sensation and perception has grown more sophisticated during the last century, new adaptive methodologies have been developed to increase efficiency and reliability of measurement. An experimental procedure is said to be adaptive if the physical characteristics of the stimuli on each trial are determined by the stimuli and responses that occurred in the previous trial or sequence of trials. In this paper, the general development of adaptive procedures is described, and three commonly used methods are reviewed. Typically, a threshold value is measured using these methods, and, in some cases, other characteristics of the psychometric function underlying perceptual performance, such as slope, may be developed. Results of simulations and experiments with human subjects are reviewed to evaluate the utility of these adaptive procedures and the special circumstances under which one might be superior to another.

Attention↗

PubMedDate not supplied

Short-term air pollution exposures and responses in Los Angeles area schoolchildren.

We studied 269 school children from three Southern California communities of contrasting air quality in two successive school years, to investigate short-term effects of ambient ozone (O3), nitrogen dioxide (NO2), or particulate matter (PM) on respiratory health. We measured lung function and symptoms twice daily for one week each in fall, winter and spring; and concurrently assessed time-activity patterns and personal exposures. Average daily personal exposures correlated with pollutant concentrations at central sites (r = 0.61 for O3, 0.63 for NO2, 0.48 for PM). Questionnaire-reported outdoor activity increased slightly in communities/seasons with higher pollution. Lung function differences between communities were explainable by age differences. Morning forced vital capacity (FVC) decreased significantly with increase in PM or NO2 measured over the preceding 24 hours. Morning-to-afternoon change of forced expired volume in one second (FEV1) became significantly more negative with increase in PM, NO2, or O3 on the same day. Predicted FVC or FEV1 loss on highest- vs lowest-pollution days was < 2%. Daily symptoms showed no association with current or prior 24-hour pollution, but increased with decreasing temperature. Parents' questionnaire responses suggested excess asthma and allergy in children from one polluted community while children in the other polluted community reported more symptoms, relative to the cleaner community. We conclude that Los Angeles area children may experience slight lung function changes in association with day-to-day air quality changes, reasonably similar to responses seen by others in less polluted areas. Although short-term pollution effects appear small, they should be assessed in longitudinal lung function studies when possible, to allow maximally accurate measurement of longer-term function changes.

Air Pollution↗

PubMed1996

Measures of uncertainty of pharmacokinetic and pharmacodynamic parameter estimates: a new computerized algorithm.

Numerous algorithms exist to fit data to nonlinear models of the type used in chemistry, pharmacology, physiology, etc. Most include modules that provide some measure of the reliability of the estimated model parameters. The variance-covariance matrix (VCM) is the common tabulation of information that is used to quantify the parameter uncertainty as well as correlations between parameters. The VCM has its mathematical foundation in the linear regression world, where the dependent variable is a linear function of the parameters. However, when the model is not linear in its parameters, then the VCM is no longer an absolute quantitative measure of reliability of the parameter estimates and should be interpreted with caution. If the goal is to obtain a realistic and quantitative rather than a qualitative measurement of the parameter reliability, then it is necessary to have an alternative approach to describe the parameter likelihood region. We present a computerized algorithm that fills that need, and we compare its performance with the traditional VCM approach for different data sets. We also discuss criteria that may be used to determine when the VCM approach should and should not be used.

Algorithms↗

PubMed2006

Checking linearity of non-parametric component in partially linear models with an application in systemic inflammatory response syndrome study.

Two tests are proposed for checking the linearity of nonparametric function in partially linear models. The first one is based on a Crámer-von Mises statistic. This test can detect the local alternative converging to the null at the parametric rate 1/square root n. A bootstrap resample technique is provided to calculate the critical values. The second one is constructed in a penalized spline framework along with linear mixed-effects (LME) modeling. This is an extension likelihood ratio test for testing zero variance of random effects in LME models. Simulation experiments are conducted to explore the numerical performance of two tests. It is observed that two tests have good level properties, and the first test has a substantially superior power property over the second test in a variety of cases. A real data set is analysed with the proposed tests.

Humans↗

PubMed1997

The tethered spinal cord in patients with anorectal malformations.

The aims of this study were to find the prevalence of tethered cord in patients with anorectal malformations; to determine if the presence of tethered cord relates to the severity of the anorectal defect, and to certain symptoms, signs, radiologic findings, and associated anomalies; and finally to determine whether tethered cord impacted on a patient's functional prognosis and whether surgical untethering improved the patient. The authors studied 934 patients with anorectal malformations, 111 of whom had magnetic resonance imaging (MRI) of the spine. We compared patients with and without tethered cord by using parametric and nonparametric statistical tests. Tethered cord occurred in 24% of the patients. The prevalence varied according to the type of anorectal defect from 43% in the complex group to 11% in patients with rectovestibular fistula. Patients with tethered cord had a lateral sacral ratio lower than that of patients without tethered cord (0.410 versus 0.702). Tethered cord was present in 90% of patients with myelodysplasia, 60% of patients with a presacral mass, 57% of patients with sacral hemivertebrae, and 56% of patients with a single kidney. The greater number of associated anomalies a patient had, the greater the risk of having tethered cord (P < .05 for all differences). The authors noted differences between patients with and without tethered cord in the presence of voluntary bowel movements (46% versus 70%), fecal soiling (91% versus 63%), constipation (21% versus 43%), and urinary incontinence (86% versus 42%). The data indicate that patients with tethered cord have a worse functional prognosis than patients without tethered cord. However, the incontinence in our patients was also predictable based on the type of anorectal defect and the character of the sacrum irrespective of the presence of tethered cord. Eighteen patients underwent surgical untethering of the cord, and none had any significant change in bowel or urinary function postoperatively. No patient with tethered cord experienced incontinence that could be attributed to the cord defect alone. This study suggests that tethered cord occurs more frequently in patients with severe anorectal defects, sacral hypodevelopment, myelodysplasia, presacral mass, sacral hemivertebrae, or a single kidney, or in those with an anorectal defect with poor functional prognosis. At present no solid evidence supports the concept that tethered cord by itself affects the functional prognosis of patients with anorectal malformations. Also, there is no good evidence demonstrating that surgical untethering improves the prognosis.

Abnormalities, Multiple↗

PubMed2005

Fine mapping of porcine chromosome 6 QTL and LEPR effects on body composition in multiple generations of an Iberian by Landrace intercross.

The leptin receptor gene (LEPR) is a candidate for traits related to growth and body composition, and is located on SSC6 in a region where fatness and meat composition quantitative trait loci (QTL) have previously been detected in several F2 experimental designs. The aims of this work were: (i) to fine map these QTL on a larger sample of animals and generations (F3 and backcross) of an Iberian x Landrace intercross and (ii) to examine the effects of LEPR alleles on body composition traits. Eleven single nucleotide polymorphisms (SNPs) were detected by sequencing LEPR coding regions in Iberian and Landrace pig samples. Three missense polymorphisms were genotyped by pyrosequencing in 33 F0, 70 F1, 418 F2, 86 F3 and 128 individuals coming from the backcross of four F2 males with 24 Landrace females. Thirteen microsatellites and one SNP were also genotyped. Traits analysed were: backfat thickness at different locations (BF(T)), intramuscular fat percentage (IMF(P)), eye muscle area (EM(A)), loin depth (LO(D)), weight of shoulder (SH(W)), weight of ribs (RIB(W)) and weight of belly bacon (BB(W)). Different statistical models were applied in order to evaluate the number and effects of QTL on chromosome 6 and the possible causality of the LEPR gene variants with respect to the QTL. The results support the presence of two QTL on SSC6. One, at position 60-100 cM, affects BF(T) and RIB(W). The other and more significant maps in a narrow region (130-132 cM) and affects BF(T), IMF(P), EM(A), LO(D), SH(W), RIB(W) and BB(W). Results also support the association between LEPR alleles and BF(T) traits. The possible functional implications of the analysed polymorphisms are considered.

Alleles↗

PubMed2005

Parallel evolution of chimeric fusion genes.

To understand how novel functions arise, we must identify common patterns and mechanisms shaping the evolution of new genes. Here, we take advantage of data from three Drosophila genes, jingwei, Adh-Finnegan, and Adh-Twain, to find evolutionary patterns and mechanisms governing the evolution of new genes. All three of these genes are independently derived from Adh, which enabled us to use the extensive literature on Adh in Drosophila to guide our analyses. We discovered a fundamental similarity in the temporal, spatial, and types of amino acid changes that occurred. All three genes underwent rapid adaptive amino acid evolution shortly after they were formed, followed by later quiescence and functional constraint. These genes also show striking parallels in which amino acids change in the Adh region. We showed that these early changes tend to occur at amino acid residues that seldom, if ever, evolve in Drosophila Adh. Changes at these slowly evolving sites are usually associated with loss of function or hypomorphic mutations in Drosophila melanogaster. Our data indicate that shifting away from ancestral functions may be a critical step early in the evolution of chimeric fusion genes. We suggest that the patterns we observed are both general and predictive.

Adaptation, Biological↗