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PubMed2005

Expiratory flow limitation is associated with orthopnea and reversed by vasodilators and diuretics in left heart failure.

BACKGROUND: In patients with acute left heart failure (LHF), orthopnea has also been related to the occurrence or worsening of expiratory flow limitation (EFL) in the supine position. We wished to assess whether short-term treatment with vasodilators and diuretics was able to abolish supine EFL and whether this could help to control orthopnea in patients with acute LHF. METHODS: In nine nonobese (ie, mean [+/- SD] body mass index, 24 +/- 5 kg/m2), never-smoker patients (two men and seven women; mean age, 77 +/- 7 years) with acute LHF (mean ejection fraction, 43 +/- 15%), we assessed EFL by the negative expiratory pressure method and dyspnea by the Borg scale, with patients in both the seated and supine positions, before and after short-term treatment with vasodilators and diuretics until hospital discharge. Orthopnea was defined as a positive difference in the Borg score between measurements made with the patient in the supine and seated positions. Postural variations in the end-expiratory lung volume were inferred from changes in inspiratory capacity (IC) that were measured under the same circumstances. RESULTS: Before treatment, with the patient in the seated position the mean dyspnea score was 1.5 +/- 0.5, the mean IC was 1.49 +/- 0.38 L, seven patients were non-flow-limited, and two patients were flow-limited. During recumbency, the mean dyspnea score was 2.7 +/- 0.5 (p < 0.01 vs seated position values), the mean IC was 1.66 +/- 0.45 L, and seven patients exhibited EFL. After a mean duration of 17 +/- 8 days of treatment (range, 7 to 28 days), EFL was detected in two patients only in the supine position, IC increased both in the seated position (1.65 +/- 0.34 L; p < 0.01) and the supine position (1.81 +/- 0.41 L; p = 0.07) position, and, although only two patients denied orthopnea, the mean dyspnea score during recumbency actually decreased to 1.9 +/- 1.0 (p < 0.05). CONCLUSIONS: Our results indicate that short-term treatment with vasodilators and diuretics is able to control orthopnea and to remove supine EFL in most patients with acute LHF, suggesting a posture-related increase in bronchial obstruction as the main mechanism of EFL, which appears to play a role in the occurrence and severity of orthopnea in these circumstances.

Aged↗
PubMed2003

"I know you self-handicapped last exam": gender differences in reactions to self-handicapping.

Past research has shown that self-handicapping involves the trade-off of ability-related attributional benefits for interpersonal costs. Study 1 examined whether perceiver or target sex moderates impressions of self-handicapping targets. Although target sex was not an important factor, female perceivers were consistently more critical of behavioral self-handicappers. Two additional studies replicated this gender difference with variations of the handicap. Study 3 examined the motives inferred by perceivers and found that women not only view self-handicappers as more unmotivated but also report greater suspicion of self-handicapping motives; furthermore, these differences in perceived motives mediated sex differences in reactions to self-handicappers. Implications for the effectiveness of self-handicapping as an impression management strategy are discussed.

Aptitude↗
PubMed2004

[18S-ITS1 sequence of rRNA in bivalves and its application in phylogenetic analysis].

Bivalves constitute a dominant and diverse group of marine animals in China, most of them are of major commercial important species, and studies of their genetic diversity are necessary for the sustainable exploitation and conservation of these bioresources. The objective of the present work is to explore the feasibility of using the ribosomal RNA as a molecular marker for studying the interspecific and intraspecific genetic variations among bivalves. The 18S-ITS1 sequences of 11 individuals at differing taxonomic levels were determined. The sequence were found to exhibit a high degree of length polymorphism among different species, ranging from 558 bp in C.farreri to 784 bp in O. rivularis, mainly resulting from the variation of ITS1, and the percent divergence ranging from 10.7% to 61.7%. The NJ (neighbor-joining) tree inferred from 18S fragment agrees with the previous study based on morphologies and chemical analysis well. The sequence variation was found to vary among 4 individuals of P. martensi (0.6% approximately 1.9%), collected from 4 geographical sites, which involved substitutions,transversion as well as insertions and deletions. All these results show that ITS1 is highly divergent among different species of bivalves and could be used in classification and distinguishing closely related species, and also could be used for molecular systematic studies at relative species, subspecies and population levels.

Animals↗
PubMed2004

A likelihood-based method for testing for nonstochastic variation of diversification rates in phylogenies.

Observed variations in rates of taxonomic diversification have been attributed to a range of factors including biological innovations, ecosystem restructuring, and environmental changes. Before inferring causality of any particular factor, however, it is critical to demonstrate that the observed variation in diversity is significantly greater than that expected from natural stochastic processes. Relative tests that assess whether observed asymmetry in species richness between sister taxa in monophyletic pairs is greater than would be expected under a symmetric model have been used widely in studies of rate heterogeneity and are particularly useful for groups in which paleontological data are problematic. Although one such test introduced by Slowinski and Guyer a decade ago has been applied to a wide range of clades and evolutionary questions, the statistical behavior of the test has not been examined extensively, particularly when used with Fisher's procedure for combining probabilities to analyze data from multiple independent taxon pairs. Here, certain pragmatic difficulties with the Slowinski-Guyer test are described, further details of the development of a recently introduced likelihood-based relative rates test are presented, and standard simulation procedures are used to assess the behavior of the two tests in a range of situations to determine: (1) the accuracy of the tests' nominal Type I error rate; (2) the statistical power of the tests; (3) the sensitivity of the tests to inclusion of taxon pairs with few species; (4) the behavior of the tests with datasets comprised of few taxon pairs; and (5) the sensitivity of the tests to certain violations of the null model assumptions. Our results indicate that in most biologically plausible scenarios, the likelihood-based test has superior statistical properties in terms of both Type I error rate and power, and we found no scenario in which the Slowinski-Guyer test was distinctly superior, although the degree of the discrepancy varies among the different scenarios. The Slowinski-Guyer test tends to be much more conservative (i.e., very disinclined to reject the null hypothesis) in datasets with many small pairs. In most situations, the performance of both the likelihood-based test and particularly the Slowinski-Guyer test improve when pairs with few species are excluded from the computation, although this is balanced against a decline in the tests' power and accuracy as fewer pairs are included in the dataset. The performance of both tests is quite poor when they are applied to datasets in which the taxon sizes do not conform to the distribution implied by the usual null model. Thus, results of analyses of taxonomic rate heterogeneity using the Slowinski-Guyer test can be misleading because the test's ability to reject the null hypothesis (equal rates) when true is often inaccurate and its ability to reject the null hypothesis when the alternative (unequal rates) is true is poor, particularly when small taxon pairs are included. Although not always perfect, the likelihood-based test provides a more accurate and powerful alternative as a relative rates test.

Biodiversity↗
PubMed2002

Sequence variations within protein families are linearly related to structural variations.

It is commonly believed that similarities between the sequences of two proteins infer similarities between their structures. Sequence alignments reliably recognize pairs of protein of similar structures provided that the percentage sequence identity between their two sequences is sufficiently high. This distinction, however, is statistically less reliable when the percentage sequence identity is lower than 30% and little is known then about the detailed relationship between the two measures of similarity. Here, we investigate the inverse correlation between structural similarity and sequence similarity on 12 protein structure families. We define the structure similarity between two proteins as the cRMS distance between their structures. The sequence similarity for a pair of proteins is measured as the mean distance between the sequences in the subsets of sequence space compatible with their structures. We obtain an approximation of the sequence space compatible with a protein by designing a collection of protein sequences both stable and specific to the structure of that protein. Using these measures of sequence and structure similarities, we find that structural changes within a protein family are linearly related to changes in sequence similarity.

Amino Acid Sequence↗
PubMed2000

Phylogeography of the European rabbit (Oryctolagus cuniculus) in the Iberian Peninsula inferred from RFLP analysis of the cytochrome b gene.

We studied mitochondrial DNA variation in the European rabbit through the examination of restriction fragment length polymorphism in 526 individuals from 20 locations spread across the Iberian Peninsula. Digestion with eight enzymes of a 1120-bp fragment comprising most of the cytochrome b gene resolved 38 different haplotypes. These haplotypes were distributed in two highly divergent clades, with different but overlapping geographical distributions, and with comparable levels of within-clade variation. The overall phylogeographical pattern suggests a history of long-term regional isolation of two groups of rabbit populations, compatible with the recognition of two subspecies within the Iberian Peninsula, followed by recent contact and admixture. The underlying cause is sought in the alternation of glacial and interglacial periods in the late Pleistocene.

Animals↗
PubMed1999

Median-joining networks for inferring intraspecific phylogenies.

Reconstructing phylogenies from intraspecific data (such as human mitochondrial DNA variation) is often a challenging task because of large sample sizes and small genetic distances between individuals. The resulting multitude of plausible trees is best expressed by a network which displays alternative potential evolutionary paths in the form of cycles. We present a method ("median joining" [MJ]) for constructing networks from recombination-free population data that combines features of Kruskal's algorithm for finding minimum spanning trees by favoring short connections, and Farris's maximum-parsimony (MP) heuristic algorithm, which sequentially adds new vertices called "median vectors", except that our MJ method does not resolve ties. The MJ method is hence closely related to the earlier approach of Foulds, Hendy, and Penny for estimating MP trees but can be adjusted to the level of homoplasy by setting a parameter epsilon. Unlike our earlier reduced median (RM) network method, MJ is applicable to multistate characters (e.g., amino acid sequences). An additional feature is the speed of the implemented algorithm: a sample of 800 worldwide mtDNA hypervariable segment I sequences requires less than 3 h on a Pentium 120 PC. The MJ method is demonstrated on a Tibetan mitochondrial DNA RFLP data set.

Algorithms↗
PubMed1984

On the statistical determination of major gene mechanisms in continuous human traits: regressive models.

We consider the analysis of a continuous trait measured on human families and pedigrees to elucidate the mechanism of underlying major genes. Thinking in terms of the naturally Markovian structure of the dependencies in pedigrees rather than variance components, we describe natural classes of regressive models that are computationally feasible. These models can accommodate wide generalizations of the residual variation, and so should provide a stronger basis than other models proposed to date for inferring the segregation and linkage relationships of major genes.

Genes↗
PubMed2005

Bayesian and maximum likelihood phylogenetic analyses of protein sequence data under relative branch-length differences and model violation.

BACKGROUND: Bayesian phylogenetic inference holds promise as an alternative to maximum likelihood, particularly for large molecular-sequence data sets. We have investigated the performance of Bayesian inference with empirical and simulated protein-sequence data under conditions of relative branch-length differences and model violation. RESULTS: With empirical protein-sequence data, Bayesian posterior probabilities provide more-generous estimates of subtree reliability than does the nonparametric bootstrap combined with maximum likelihood inference, reaching 100% posterior probability at bootstrap proportions around 80%. With simulated 7-taxon protein-sequence datasets, Bayesian posterior probabilities are somewhat more generous than bootstrap proportions, but do not saturate. Compared with likelihood, Bayesian phylogenetic inference can be as or more robust to relative branch-length differences for datasets of this size, particularly when among-sites rate variation is modeled using a gamma distribution. When the (known) correct model was used to infer trees, Bayesian inference recovered the (known) correct tree in 100% of instances in which one or two branches were up to 20-fold longer than the others. At ratios more extreme than 20-fold, topological accuracy of reconstruction degraded only slowly when only one branch was of relatively greater length, but more rapidly when there were two such branches. Under an incorrect model of sequence change, inaccurate trees were sometimes observed at less extreme branch-length ratios, and (particularly for trees with single long branches) such trees tended to be more inaccurate. The effect of model violation on accuracy of reconstruction for trees with two long branches was more variable, but gamma-corrected Bayesian inference nonetheless yielded more-accurate trees than did either maximum likelihood or uncorrected Bayesian inference across the range of conditions we examined. Assuming an exponential Bayesian prior on branch lengths did not improve, and under certain extreme conditions significantly diminished, performance. The two topology-comparison metrics we employed, edit distance and Robinson-Foulds symmetric distance, yielded different but highly complementary measures of performance. CONCLUSIONS: Our results demonstrate that Bayesian inference can be relatively robust against biologically reasonable levels of relative branch-length differences and model violation, and thus may provide a promising alternative to maximum likelihood for inference of phylogenetic trees from protein-sequence data.

Bayes Theorem↗
PubMed1992

Sequestered end products and enzyme regulation: the case of ornithine decarboxylase.

The polyamines (putrescine, spermidine, and spermine) are synthesized by almost all organisms and are universally required for normal growth. Ornithine decarboxylase (ODC), an initial enzyme of polyamine synthesis, is one of the most highly regulated enzymes of eucaryotic organisms. Unusual mechanisms have evolved to control ODC, including rapid, polyamine-mediated turnover of the enzyme and control of the synthetic rate of the protein without change of its mRNA level. The high amplitude of regulation and the rapid variation in the level of the protein led biochemists to infer that polyamines had special cellular roles and that cells maintained polyamine concentrations within narrow limits. This view was sustained in part because of our continuing uncertainty about the actual biochemical roles of polyamines. In this article, we challenge the view that ODC regulation is related to precise adjustment of polyamine levels. In no organism does ODC display allosteric feedback inhibition, and in three types of organism, bacteria, fungi, and mammals, the size of polyamine pools may vary radically without having a profound effect on growth. We suggest that the apparent stability of polyamine pools in unstressed cells is due to their being largely bound to cellular polyanions. We further speculate that allosteric feedback inhibition, if it existed, would be inappropriately responsive to changes in the small, freely diffusible polyamine pool. Instead, mechanisms that control the amount of the ODC protein have appeared in most organisms, and even these are triggered inappropriately by variation of the binding of polyamines to ionic binding sites. In fact, feedback inhibition of ODC might be maladaptive during hypoosmotic stress or at the onset of growth, when organisms appear to require rapid increases in the size of their cellular polyamine pools.

Animals↗
PubMed2003

A survey of chromosomal and nucleotide sequence variation in Drosophila miranda.

There have recently been several studies of the evolution of Y chromosome degeneration and dosage compensation using the neo-sex chromosomes of Drosophila miranda as a model system. To understand these evolutionary processes more fully, it is necessary to document the general pattern of genetic variation in this species. Here we report a survey of chromosomal variation, as well as polymorphism and divergence data, for 12 nuclear genes of D. miranda. These genes exhibit varying levels of DNA sequence polymorphism. Compared to its well-studied sibling species D. pseudoobscura, D. miranda has much less nucleotide sequence variation, and the effective population size of this species is inferred to be several-fold lower. Nevertheless, it harbors a few inversion polymorphisms, one of which involves the neo-X chromosome. There is no convincing evidence for a recent population expansion in D. miranda, in contrast to D. pseudoobscura. The pattern of population subdivision previously observed for the X-linked gene period is not seen for the other loci, suggesting that there is no general population subdivision in D. miranda. However, data on an additional region of period confirm population subdivision for this gene, suggesting that local selection is operating at or near period to promote differentiation between populations.

Alleles↗
PubMed2005

Bioinformatics approaches and resources for single nucleotide polymorphism functional analysis.

Since the initial sequencing of the human genome, many projects are underway to understand the effects of genetic variation between individuals. Predicting and understanding the downstream effects of genetic variation using computational methods are becoming increasingly important for single nucleotide polymorphism (SNP) selection in genetics studies and understanding the molecular basis of disease. According to the NIH, there are now more than four million validated SNPs in the human genome. The volume of known genetic variations lends itself well to an informatics approach. Bioinformaticians have become very good at functional inference methods derived from functional and structural genomics. This review will present a broad overview of the tools and resources available to collect and understand functional variation from the perspective of structure, expression, evolution and phenotype. Additionally, public resources available for SNP identification and characterisation are summarised.

Algorithms↗
PubMed2005

Comparison of single-nucleotide polymorphisms and microsatellites in inference of population structure.

Single-nucleotide polymorphisms (SNPs) are a class of attractive genetic markers for population genetic studies and for identifying genetic variations underlying complex traits. However, the usefulness and efficiency of SNPs in comparison to microsatellites in different scientific contexts, e.g., population structure inference or association analysis, still must be systematically evaluated through large empirical studies. In this article, we use the Collaborative Studies on Genetics of Alcoholism (COGA) data from Genetic Analysis Workshop 14 (GAW14) to compare the performance of microsatellites and SNPs in the whole human genome in the context of population structure inference. A total of 328 microsatellites and 15,840 SNPs are used to infer population structure in 236 unrelated individuals. We find that, on average, the informativeness of random microsatellites is four to twelve times that of random SNPs for various population comparisons, which is consistent with previous studies. Our results also indicate that for the combined set of microsatellites and SNPs, SNPs constitute the majority among the most informative markers and the use of these SNPs leads to better inference of population structure than the use of microsatellites. We also find that the inclusion of less informative markers may add noise and worsen the results.

Genetic Loci↗
PubMed2003

Tooth-root form and function in platyrrhine seed-eaters.

Research into the functional and adaptive basis of tooth crown form has provided a useful framework for the inference of diet in extinct primates. However, our understanding of variation in tooth-root form is limited. Studies within the clinical literature emphasize the influence of tooth-root surface area on stress resistance, but it is not known if root form has diversified during primate evolution in relation to dietary specialization. This hypothesis was tested by quantifying maxillary canine and postcanine tooth-root surface areas in four platyrrhine species that differ in the material properties of their diet: Cebus apella, Cebus albifrons, Chiropotes satanas, and Pithecia pithecia. Pairwise comparisons between closely related taxa support predictions based on dietary differences. Taxa that regularly consume resistant seeds (Cebus apella and Chiropotes satanas) exhibit significantly larger relative surface area values for those teeth used in seed processing than closely related taxa that consume resistant foods less often (Cebus albifrons and Pithecia pithecia). Additionally, relative molar-root surface area appears to be greater in Pithecia than in Chiropotes, as predicted from the more folivorous diet of Pithecia. Tooth-root surface area was also found to vary along the tooth row and should therefore have a significant influence on antero-posterior bite-force gradients. The results of this study suggest a close relationship between tooth-root form and patterns of occlusal loading. Further elucidation of this relationship could improve our inferences of diet in extinct taxa, and augment research into the mechanics and evolution of feeding.

Animals↗
PubMed2000

mtDNA hypervariable region II (HVII) sequences in human evolution studies.

Variation in human mitochondrial DNA (mtDNA) has been used to infer the origin and migration patterns in human populations. mtDNA analysis has been focused mainly on the first hypervariable region (HVI). Nevertheless, although many studies of the second hypervariable region (HVII) have been carried out during recent years, the correlation between the first and the second hypervariable regions has not been well established. We have analysed 71 individuals from a relatively isolated region at the westernmost edge of continental Europe (Galicia, NW Iberian peninsula) and we have used available HVII sequence information from another 17 European and African populations. The results show high concordance between the two hypervariable regions, not only in variability levels but also in other phylogenetic aspects. The study of the population structure through an AMOVA analysis shows a low level of heterogeneity in the European populations. Nevertheless, we have found some inconsistency in the results, which are related to the mutation rate in these two hypervariable regions. These results are compatible with a high heterogeneity of mutation rates across the HVII region and stress the interest of HVII in population and forensic genetics.

Base Sequence↗
PubMed1999

Variational learning in nonlinear gaussian belief networks.

We view perceptual tasks such as vision and speech recognition as inference problems where the goal is to estimate the posterior distribution over latent variables (e.g., depth in stereo vision) given the sensory input. The recent flurry of research in independent component analysis exemplifies the importance of inferring the continuous-valued latent variables of input data. The latent variables found by this method are linearly related to the input, but perception requires nonlinear inferences such as classification and depth estimation. In this article, we present a unifying framework for stochastic neural networks with nonlinear latent variables. Nonlinear units are obtained by passing the outputs of linear gaussian units through various nonlinearities. We present a general variational method that maximizes a lower bound on the likelihood of a training set and give results on two visual feature extraction problems. We also show how the variational method can be used for pattern classification and compare the performance of these nonlinear networks with other methods on the problem of handwritten digit recognition.

Depth Perception↗
PubMed2006

Constraining a possible time variation of the gravitational constant through "gravitochemical heating" of neutron stars.

A hypothetical time variation of the gravitational constant G would cause neutron star matter to depart from beta equilibrium, due to the changing hydrostatic equilibrium. This induces nonequilibrium beta processes, which release energy that is invested partly in neutrino emission and partly in internal heating. Eventually, the star arrives at a stationary state in which the temperature remains nearly constant, as the forcing through the change of G is balanced by the ongoing reactions. Using the surface temperature of the nearest millisecond pulsar, PSR J0437-4715, inferred from ultraviolet observations, we estimate two upper limits for this variation: (1) |.G/G|< 2 x 10(-10) yr(-1), if direct Urca reactions are allowed, and (2) |.G/G|< 4 x 10(-12) yr(-1), considering only modified Urca reactions. The latter is among the most restrictive obtained by other methods.

Journal Article↗
PubMed1996

Length variation, heteroplasmy and sequence divergence in the mitochondrial DNA of four species of sturgeon (Acipenser).

The extent of mtDNA length variation and heteroplasmy as well as DNA sequences of the control region and two tRNA genes were determined for four North American sturgeon species: Acipenser transmontanus, A. medirostris, A. fulvescens and A. oxyrhnychus. Across the Continental Divide, a division in the occurrence of length variation and heteroplasmy was observed that was concordant with species biogeography as well as with phylogenies inferred from restriction fragment length polymorphisms (RFLP) of whole mtDNA and pairwise comparisons of unique sequences of the control region. In all species, mtDNA length variation was due to repeated arrays of 78-82-bp sequences each containing a D-loop strand synthesis termination associated sequence (TAS). Individual repeats showed greater sequence conservation within individuals and species rather than between species, which is suggestive of concerted evolution. Differences in the frequencies of multiple copy genomes and heteroplasmy among the four species may be ascribed to differences in the rates of recurrent mutation. A mechanism that may offset the high rate of mutation for increased copy number is suggested on the basis that an increase in the number of functional TAS motifs might reduce the frequency of successfully initiated H-strand replications.

Animals↗