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PubMed2006

Genome-wide survey for biologically functional pseudogenes.

According to current estimates there exist about 20,000 pseudogenes in a mammalian genome. The vast majority of these are disabled and nonfunctional copies of protein-coding genes which, therefore, evolve neutrally. Recent findings that a Makorin1 pseudogene, residing on mouse Chromosome 5, is, indeed, in vivo vital and also evolutionarily preserved, encouraged us to conduct a genome-wide survey for other functional pseudogenes in human, mouse, and chimpanzee. We identify to our knowledge the first examples of conserved pseudogenes common to human and mouse, originating from one duplication predating the human-mouse species split and having evolved as pseudogenes since the species split. Functionality is one possible way to explain the apparently contradictory properties of such pseudogene pairs, i.e., high conservation and ancient origin. The hypothesis of functionality is tested by comparing expression evidence and synteny of the candidates with proper test sets. The tests suggest potential biological function. Our candidate set includes a small set of long-lived pseudogenes whose unknown potential function is retained since before the human-mouse species split, and also a larger group of primate-specific ones found from human-chimpanzee searches. Two processed sequences are notable, their conservation since the human-mouse split being as high as most protein-coding genes; one is derived from the protein Ataxin 7-like 3 (ATX7NL3), and one from the Spinocerebellar ataxia type 1 protein (ATX1). Our approach is comparative and can be applied to any pair of species. It is implemented by a semi-automated pipeline based on cross-species BLAST comparisons and maximum-likelihood phylogeny estimations. To separate pseudogenes from protein-coding genes, we use standard methods, utilizing in-frame disablements, as well as a probabilistic filter based on Ka/Ks ratios.

Animals↗

PubMed2001

Functional diversification of lepidopteran opsins following gene duplication.

A comparative approach was taken for identifying amino acid substitutions that may be under positive Darwinian selection and are correlated with spectral shifts among orthologous and paralogous lepidopteran long wavelength-sensitive (LW) opsins. Four novel LW opsin fragments were isolated, cloned, and sequenced from eye-specific cDNAs from two butterflies, Vanessa cardui (Nymphalidae) and Precis coenia (Nymphalidae), and two moths, Spodoptera exigua (Noctuidae) and Galleria mellonella (Pyralidae). These opsins were sampled because they encode visual pigments having a naturally occurring range of lambda(max) values (510-530 nm), which in combination with previously characterized lepidopteran opsins, provide a complete range of known spectral sensitivities (510-575 nm) among lepidopteran LW opsins. Two recent opsin gene duplication events were found within the papilionid but not within the nymphalid butterfly families through neighbor-joining, maximum parsimony, and maximum likelihood phylogenetic analyses of 13 lepidopteran opsin sequences. An elevated rate of evolution was detected in the red-shifted Papilio Rh3 branch following gene duplication, because of an increase in the amino acid substitution rate in the transmembrane domain of the protein, a region that forms the chromophore-binding pocket of the visual pigment. A maximum likelihood approach was used to estimate omega, the ratio of nonsynonymous to synonymous substitutions per site. Branch-specific tests of selection (free-ratio) identified one branch with omega = 2.1044, but the small number of substitutions involved was not significantly different from the expected number of changes under the neutral expectation of omega = 1. Ancestral sequences were reconstructed with a high degree of certainty from these data. Reconstructed ancestral sequences revealed several instances of convergence to the same amino acid between butterfly and vertebrate cone pigments, and between independent branches of the butterfly opsin tree that are correlated with spectral shifts.

Amino Acid Sequence↗

PubMed2006

Molecular evolution of the puroindoline-a, puroindoline-b, and grain softness protein-1 genes in the tribe Triticeae.

The genome organization of the Hardness locus in the tribe Triticeae constitutes an excellent model for studying the mechanisms of evolution that played a role in the preservation and potential functional innovations of duplicate genes. Here we applied the nonsynonymous-synonymous rate ratio (d ( N )/d ( S ) or omega) to measure the selective pressures at the paralogous puroindoline-a (Pina), puroindoline-b (Pinb), and grain softness protein-1 (Gsp-1) genes located at this locus. Puroindolines represent the molecular-genetic basis of grain texture. In addition, the puroindoline gene products have antimicrobial properties with potential role in plant defense. We document the complete coding sequences from the Triticum/Aegilops taxa, rye and barley including the A, D, C, H, M, N, R, S, and U genomes of the Triticeae. Maximum likelihood analyses performed on Bayesian phylogenetic trees showed distinct evolutionary patterns among Pina, Pinb, and Gsp-1. Positive diversifying selection appeared to drive the evolution of at least one of the three genes examined, suggesting that adaptive forces have operated at this locus. Results evidenced positive selection (omega > 4) at Pina and detected amino acid residues along the mature PIN-a protein with a high probability (>95%) of having evolved under adaptation. We hypothesized that positive selection at the Pina region is congruent with its role as a plant defense gene.

Amino Acid Sequence↗

PubMed1994

Clinical predictors of successful implantable cardioverter defibrillator implantation.

Successful implantation of an implantable cardioverter defibrillation system is critically dependent on demonstration that the lead system to be implanted can defibrillate reliably. Defibrillation efficacy in turn is dependent on several sets of factors that include: (1) defibrillation technique and the lead system being tested; (2) defibrillation testing protocol and criteria for implantation; and (3) clinical variables that may be intrinsic to the patient or extrinsic factors to which the patient is being exposed. Existing clinical data are limited but suggest that poor left ventricular function is the clinical variable most consistently associated with poor defibrillation efficacy and a failure to meet implant criteria of the epicardial lead systems. Antiarrhythmic drugs may elevate the defibrillation threshold, but evidence that this has important clinical ramifications on implantation success rates is very limited and incomplete.

Anti-Arrhythmia Agents↗

PubMed2006

Predicting caregiver assistance required for sit-to-stand following rehabilitation for acute stroke.

OBJECTIVE/METHODS: The objective of this case series was to determine the relationship between impairments identified at hospital admission and a reduced need for sit-to-stand (STS) assistance during an inpatient rehabilitation hospital stay. Fifty- five inpatients with a diagnosis of acute stroke were retrospectively studied. Demographic information and the following admission and discharge measures were collected from a chart review: bilateral dorsiflexion PROM, strength of the unaffected leg, Motricity Index (MI), presence of hemi-neglect, gait velocity, and Functional Independence Measure (FIM) scores for STS, ambulation, and cognition. Sit to stand improvement was determined by a change of at least one Caregiver Assistance Level (CAL) in STS performance between hospital admission and discharge. CAL 1 = STS FIM score of 7 or 6; CAL 2 = STS FIM score of 5; CAL 3 = STS FIM score of 4, 3, 2, or 1. RESULTS: Unaffected knee extension strength, Motricity Index (MI) score, FIM cognition scores, and bilateral ankle dorsiflexion PROM were each univariate, age-adjusted predictors of improvement in STS CAL. A multivariate, 3 main-effect model that included admission FIM cognitive scores and ankle PROM correctly predicted 90.6% (48 out of 53) of the possible sit to stand improvement outcomes. Admission gait velocity and MI differentiated extent of functional change in those who improved. CONCLUSIONS: Cognition and bilateral ankle dorsiflexion PROM most strongly predicted STS CAL improvement during an inpatient rehabilitation stay. Caregivers of patients with significant impairments may benefit from early and intensive training on how to assist their family member in the STS task.

Activities of Daily Living↗

PubMed1999

Symmetric tests and confidence intervals for survival probabilities and quantiles of censored survival data.

We describe existing tests and introduce two new tests concerning the value of a survival function. These tests may be used to construct a confidence interval for the survival probability at a given time or for a quantile of the survival distribution. Simulation studies show that error rates can differ substantially from their nominal values, particularly at survival probabilities close to zero or one. We recommend our new constrained bootstrap test for its good overall performance.

Biometry↗

PubMed2001

Quantitative dose-volume response analysis of changes in parotid gland function after radiotherapy in the head-and-neck region.

PURPOSE: To study the radiation tolerance of the parotid glands as a function of dose and volume irradiated. METHODS AND MATERIALS: One hundred eight patients treated with primary or postoperative radiotherapy for various malignancies in the head-and-neck region were prospectively evaluated. Stimulated parotid flow rate was measured before radiotherapy and 6 weeks, 6 months, and 1 year after radiotherapy. Parotid gland dose-volume histograms were derived from CT-based treatment planning. The normal tissue complication probability model proposed by Lyman was fit to the data. A complication was defined as stimulated parotid flow rate <25% of the preradiotherapy flow rate. RESULTS: The mean stimulated preradiotherapy flow rate of 174 parotid glands was 0.34 mL/min. The mean flow rate reduced to 0.12 mL/min 6 weeks postradiotherapy, but recovered to a mean flow rate of 0.20 mL/min at 1 year after radiotherapy. Reduction in postradiotherapy flow rate correlated significantly with mean parotid dose. No threshold dose was found. Increasing the irradiated volume of parotid glands from 0%-40% to 90-100% in patients with a mean parotid dose of 35-45 Gy resulted in a decrease in flow ratio from, respectively, approximately 100% to less than 10% 6 weeks after radiation. The flow ratio of the 90%-100% group partially recovered to 15% at 6 months and to 30% at 1 year after radiotherapy. The normal tissue complication probability model parameter TD(50) (the dose to the whole organ leading to a complication probability of 50%) was found to be 31, 35, and 39 Gy at 6 weeks, 6 months, and 1 year postradiotherapy, respectively. The volume dependency parameter n was around 1, which means that the mean parotid dose correlates best with the observed complications. There was no steep dose-response curve (m = 0.45 at 1 year postradiotherapy). CONCLUSIONS: This study on dose/volume/parotid gland function relationships revealed a linear correlation between postradiotherapy flow ratio and parotid gland dose and a strong volume dependency. No threshold dose was found. Recovery of parotid gland function was shown at 6 months and 1 year after radiotherapy. In radiation planning, attempts should be made to achieve a mean parotid gland dose at least below 39 Gy (leading to a complication probability of 50%).

Adult↗

PubMed2004

Molecular evolution of plant haemoglobin: two haemoglobin genes in Nymphaeaceae Euryale ferox.

We isolated and sequenced two haemoglobin genes from the early-branching angiosperm Euryale ferox (Nymphaeaceae). The two genes belong to the two known classes of plant haemoglobin. Their existence in Nymphaeaceae supports the theory that class 1 haemoglobin was ancestrally present in all angiosperms, and is evidence for class 2 haemoglobin being widely distributed. These sequences allowed us to unambiguously root the angiosperm haemoglobin phylogeny, and to corroborate the hypothesis that the class 1/class 2 duplication event occurred before the divergence between monocots and eudicots. We addressed the molecular evolution of plant haemoglobin by comparing the synonymous and nonsynonymous substitution rates in various groups of genes. Class 2 haemoglobin genes of legumes (functionally involved in a symbiosis with nitrogen-fixing bacteria) show a higher nonsynonymous substitution rate than class 1 (nonsymbiotic) haemoglobin genes. This suggests that a change in the selective forces applying to plant haemoglobins has occurred during the evolutionary history of this gene family, potentially in relation with the evolution of symbiosis.

Bayes Theorem↗

PubMed2005

Adaptive snakes using the EM algorithm.

Deformable models (e.g., snakes) perform poorly in many image analysis problems. The contour model is attracted by edge points detected in the image. However, many edge points do not belong to the object contour, preventing the active contour from converging toward the object boundary. A new algorithm is proposed in this paper to overcome this difficulty. The algorithm is based on two key ideas. First, edge points are associated in strokes. Second, each stroke is classified as valid (inlier) or invalid (outlier) and a confidence degree is associated to each stroke. The expectation maximization algorithm is used to update the confidence degrees and to estimate the object contour. It is shown that this is equivalent to the use of an adaptive potential function which varies during the optimization process. Valid strokes receive high confidence degrees while confidence degrees of invalid strokes tend to zero during the optimization process. Experimental results are presented to illustrate the performance of the proposed algorithm in the presence of clutter, showing a remarkable robustness.

Algorithms↗

PubMed2003

A spatiotemporal stochastic process model for species spread.

We use a spatiotemporal Markov process to model the spread of an ecological population through its environment over time. Available habitat is divided into sites, and a parametric function of spatial variables is used to model the probability that one site is colonized from another. This allows us both to make predictions about the future spread of a population, and to determine which are the important factors governing colonizations. The model evolves in discrete time, allowing the population distribution to change seasonally in accordance with breeding patterns. Discrete time formulations are natural for ecological populations, but are problematic due to difficulties of fitting and predicting over irregular time intervals. The model described here can accommodate years of missing data and can therefore fit and predict at irregular intervals. Two methods of approximating the likelihood are described and applied to ornithological survey data for the woodlark, Lullula arborea, from Thetford Forest in the U.K.

Animals↗

PubMedDate not supplied

nanos expression at the embryonic posterior pole and the medusa phase in the hydrozoan Podocoryne carnea.

Summary The distinction between soma and germline is an important process in the development of animals with sexual reproduction. It is regulated by a number of germline-specific genes, most of which appear conserved in evolution and therefore can be used to study the formation of the germline in diverged animal groups. Here we report the isolation of two orthologs of one such gene, nanos (nos), in the cnidarian Podocoryne carnea, a species with representative zoological features among the hydrozoans. By studying nos gene expression throughout the Podocoryne biphasic life cycle, we find that the germline differentiates exclusively during medusa development, whereas the polyp does not contribute to the process. An early widespread nos expression in developing medusae progressively refines into a mainly germline-specific pattern at terminal stages of medusa formation. Thus, the distinction between germline and soma is a late event in hydrozoan development. Also, we show that the formation of the medusa is a de novo process that relies on active local cell proliferation and differentiation of novel cell and tissue types not present in the polyp, including nos-expressing cells. Finally, we find nos expression at the posterior pole of Podocoryne developing embryos, not related to germline formation. This second aspect of nos expression is also found in Drosophila, where nos functions as a posterior determinant essential for the formation of the fly abdomen. This raises the possibility that nos embryonic expression could play a role in establishing axial polarity in cnidarians.

Amino Acid Sequence↗

PubMed1993

Frequency domain dipole localization: extensions of the method and applications to auditory and visual evoked potentials.

We describe a statistical frequency domain approach to localizing equivalent dipole generators of human brain evoked potentials. The frequency domain representation allows considerable data reduction, constrains the magnitude function of the dipoles to be smooth, and accounts for the statistical properties of the background EEG. A previous paper described a restrictive model in which the dipole orientations were assumed to be fixed over time, and only one dipole was allowed. In this paper, we consider the more general model in which the orientation can vary over time, and which includes multiple dipole generators. The varying orientation model has the practical advantage of being more nearly linear and more flexible than the fixed orientation model, which facilitates convergence of the iterative fitting algorithm. We suggest a measure of goodness-of-fit that compares the likelihood of the dipole model with the likelihoods of saturated and null models. We report the results of fitting the model to recorded auditory and visual evoked potentials. A single dipole with fixed orientation seems to be an adequate model of the auditory midlatency response, while two dipoles with varying orientation are needed to fit the later P200 component. Analysis of the visual P100 response to unilateral stimulation localized a generator in the contralateral occipital cortex, as expected from anatomical considerations. A two-dipole model fit the visual P100 response of bilateral stimulations, and the locations of the two dipoles were similar to the locations obtained by single-dipole fits to the responses to left and right unilateral stimuli.

Computer Simulation↗

PubMed2006

Relationship between nursing interventions and outcome achievement in acute care settings.

The extent to which nursing interventions provided during hospitalization are associated with patients' therapeutic self-care and functional health outcomes was explored with a voluntary sample of 574 patients. Nurses collected data on patient outcomes at admission and discharge using the minimum data set (MDS) and the therapeutic self-care scale (TSCS). Research assistants audited charts for documentation of nursing interventions. The results indicated that nursing interventions aimed at exercise promotion, positioning, and self-care assistance predicted functional status outcome. Higher functional status outcome predicted therapeutic self-care ability at hospital discharge. The results demonstrate that nurses can use MDS and TSCS data on patient outcomes to gain insight into the effectiveness of their interventions.

Activities of Daily Living↗

PubMed2004

Evolutionary analysis of the two-component systems in Pseudomonas aeruginosa PAO1.

Gene organization and functional motif analyses of the 123 two-component system (2CS) genes in Pseudomonas aeruginosa PAO1 were carried out. In addition, NJ and ML trees for the sensor kinases and the response regulators were constructed, and the distances measured and comparatively analyzed. It was apparent that more than half of the sensor-regulator gene pairs, especially the 2CSs with OmpR-like regulators, are derivatives of a common ancestor and have most likely co-evolved through gene pair duplication. Several of the 2CS pairs, especially those with NarL-like regulators, however, appeared to be relatively divergent. This is supportive of the recruitment model, in which a sensor gene and regulator gene with different phylogenetic history are assembled to form a 2CS. Correlation of the classification of sensor kinases and response regulators provides further support for these models. Upon comparison of the phylogenetic trees comprised of sensors and regulators, we have identified six congruent clades, which represent the group of the most recently duplicated 2CS gene pairs. Analyses of the congruent 2CS pairs of each of the clades revealed that certain paralogous 2CS pairs may carry a redundant function even after a gene duplication event. Nevertheless, comparative analysis of the putative promoter regions of the paralogs suggested that functional redundancy could be prevented by a differential control. Both codon usage and G+C content of these 2CS genes were found to be comparable with those of the P. aeruginosa genome, suggesting that they are not newly acquired genes.

Base Composition↗

PubMed2004

Propagation of errors from the sensitivity image in list mode reconstruction.

List mode image reconstruction is attracting renewed attention. It eliminates the storage of empty sinogram bins. However, a single back projection of all LORs is still necessary for the pre-calculation of a sensitivity image. Since the detection sensitivity is dependent on the object attenuation and detector efficiency, it must be computed for each study. Exact computation of the sensitivity image can be a daunting task for modern scanners with huge numbers of LORs. Thus, some fast approximate calculation may be desirable. In this paper, we analyze the error propagation from the sensitivity image into the reconstructed image. The theoretical analysis is based on the fixed point condition of the list mode reconstruction. The nonnegativity constraint is modeled using the Kuhn-Tucker condition. With certain assumptions and the first-order Taylor series approximation, we derive a closed form expression for the error in the reconstructed image as a function of the error in the sensitivity image. The result shows that the error response is frequency-dependent and provides a simple expression for determining the required accuracy of the sensitivity image calculation. Computer simulations show that the theoretical results are in good agreement with the measured results.

Algorithms↗

PubMed2005

Lineage-specific variations of congruent evolution among DNA sequences from three genomes, and relaxed selective constraints on rbcL in Cryptomonas (Cryptophyceae).

BACKGROUND: Plastid-bearing cryptophytes like Cryptomonas contain four genomes in a cell, the nucleus, the nucleomorph, the plastid genome and the mitochondrial genome. Comparative phylogenetic analyses encompassing DNA sequences from three different genomes were performed on nineteen photosynthetic and four colorless Cryptomonas strains. Twenty-three rbcL genes and fourteen nuclear SSU rDNA sequences were newly sequenced to examine the impact of photosynthesis loss on codon usage in the rbcL genes, and to compare the rbcL gene phylogeny in terms of tree topology and evolutionary rates with phylogenies inferred from nuclear ribosomal DNA (concatenated SSU rDNA, ITS2 and partial LSU rDNA), and nucleomorph SSU rDNA. RESULTS: Largely congruent branching patterns and accelerated evolutionary rates were found in nucleomorph SSU rDNA and rbcL genes in a clade that consisted of photosynthetic and colorless species suggesting a coevolution of the two genomes. The extremely accelerated rates in the rbcL phylogeny correlated with a shift from selection to mutation drift in codon usage of two-fold degenerate NNY codons comprising the amino acids asparagine, aspartate, histidine, phenylalanine, and tyrosine. Cysteine was the sole exception. The shift in codon usage seemed to follow a gradient from early diverging photosynthetic to late diverging photosynthetic or heterotrophic taxa along the branches. In the early branching taxa, codon preferences were changed in one to two amino acids, whereas in the late diverging taxa, including the colorless strains, between four and five amino acids showed changes in codon usage. CONCLUSION: Nucleomorph and plastid gene phylogenies indicate that loss of photosynthesis in the colorless Cryptomonas strains examined in this study possibly was the result of accelerated evolutionary rates that started already in photosynthetic ancestors. Shifts in codon usage are usually considered to be caused by changes in functional constraints and in gene expression levels. Thus, the increasing influence of mutation drift on codon usage along the clade may indicate gradually relaxed constraints and reduced expression levels on the rbcL gene, finally correlating with a loss of photosynthesis in the colorless Cryptomonas paramaecium strains.

Asparagine↗

PubMed2001

Group comparisons involving missing data in clinical trials: a comparison of estimates and power (size) for some simple approaches.

When using 'intent-to-treat' approaches to compare outcomes between groups in clinical trials, analysts face a decision regarding how to account for missing observations. Most model-based approaches can be summarized as a process whereby the analyst makes assumptions about the distribution of the missing data in an attempt to obtain unbiased estimates that are based on functions of the observed data. Although pointed out by Rubin as often leading to biased estimates of variances, an alternative approach that continues to appear in the applied literature is to use fixed-value imputation of means for missing observations. The purpose of this paper is to provide illustrations of how several fixed-value mean imputation schemes can be formulated in terms of general linear models that characterize the means of distributions of missing observations in terms of the means of the distributions of observed data. We show that several fixed-value imputation strategies will result in estimated intervention effects that correspond to maximum likelihood estimates obtained under analogous assumptions. If the missing data process has been correctly characterized, hypothesis tests based on variances estimated using maximum likelihood techniques asymptotically have the correct size. In contrast, hypothesis tests performed using the uncorrected variance, obtained by applying standard complete data formula to singly imputed data, can provide either conservative or anticonservative results. Surprisingly, under several non-ignorable non-response scenarios, maximum likelihood based analyses can yield equivalent hypothesis tests to those obtained when analysing only the observed data.

Aged↗

PubMed2000

Genomic sequence analysis of the mouse Naip gene array.

A mouse locus called Lgn1 determines differences in macrophage permissiveness for the intracellular replication of Legionella pneumophila. The only regional candidate genes for this phenotype difference lie within a cluster of closely linked paralogs of the Neuronal Apoptosis Inhibitory Protein (Naip) gene. Previous genetic and physical mapping of the Lgn1 phenotype narrowed it to an interval containing only Naip2 and Naip5, suggesting that there is not complete functional overlap among the mouse Naip loci. In order to gather more information about polymorphisms among the Naip genes of the 129 mouse haplotype, we have determined the genomic sequence of a substantial portion of the 129 Naip gene array. We have constructed an evolutionary model for the expansion of the Naip gene array from a single progenitor Naip gene. This model predicts the presence of two distinct families of Naip paralogs: Naip1/2/3 and Naip4/5/6/7. Unlike the divergences among all the other Naip paralogs, the splits among Naip4, Naip5, Naip6, and Naip7 occurred relatively recently. The high degree of sequence conservation within the Naip4/5/6/7 family increases the likelihood of functional overlap among these genes.

Animals↗