Clustering of identical oligomers in coding and noncoding DNA sequences.

We develop a quantitative method for analyzing repetitions of identical short oligomers in coding and noncoding DNA sequences. We analyze sequences presently available in the GenBank separately for primate, mammal, vertebrate, rodent, invertebrate and plant taxonomic partitions. We find that some oligomers "cluster" more than they would if randomly distributed, while other oligomers "repel" each other. To quantify this degree of clustering, we define clustering measures. We find that (i) clustering significantly differs in coding and noncoding DNA; (ii) in most cases, monomers, dimers and tetramers cluster in noncoding DNA but appear to repel each other in coding DNA. (iii) The degree of clustering for different sources (primates, invertebrates, and plants) is more conserved among these sources in the case of coding DNA than in the case of noncoding DNA. (iv) In contrast to other oligomers, we find that trimers always prefer to cluster. (v) Clustering of each particular oligomer is conserved within the same organism.     

Motifer, a search tool for finding amino acid sequence patterns from nucleotide sequence databases.

Motifer is a software tool able to find directly in nucleotide databases very distant homologues to an amino acid query sequence. It focuses searches on a specific amino acid pattern, scoring the matching and intervening residues as specified by the user. The program has been developed for searching databases of expressed sequence tags (ESTs), but it is also well suited to search genomic sequences. The query sequence can be a variable pattern with alternative amino acids or gaps and the sequences searched can contain introns or sequencing errors with accompanying frame shifts. Other features include options to generate a searchable output, set the maximal sequencing error frequency, limit searches to given species, or exclude already known matches. Motifer can find sequence homologues that other search algorithms would deem unrelated or would not find because of sequencing errors or a too large number of other homologues. The ability of Motifer to find relatives to a given sequence is exemplified by searches for members of the transforming growth factor-beta family and for proteins containing a WW-domain. The functions aimed at enhancing EST searches are illustrated by the 'in silico' cloning of a novel cytochrome P450 enzyme.     

MatchMiner: a tool for batch navigation among gene and gene product identifiers

MatchMiner is a freely available program package for batch navigation among gene and gene product identifier types commonly encountered in microarray studies and other forms of 'omic' research. The user inputs a list of gene identifiers and then uses the Merge function to find the overlap with a second list of identifiers of either the same or a different type or uses the LookUp function to find corresponding identifiers.     

A computer model for learning processes and the role of the cerebral commissures

A computer model of the two brain hemispheres is constructed of discrete populations of neurons, and it is shown to exhibit the characteristics of the great cerebral commissures, as has been pointed out by Sperry and others. For the range of parameters used we find that such systems respond in a specific manner to specific stimuli, and furthermore, whatever memory is transferred to one simulated hemisphere is also transferred to the other. However, this behavior changes when the two hemispheres are separated. We find that memory is not transferred from one hemisphere to the other when the interconnecting commissures are severed. The above findings verify Sperry's experimental observation that the split brain behaves as if it were indeed two separate brains, each performing concurrently and simultaneously diametrically opposite tasks.     

Failure to detect seasonal changes in the song system nuclei of the black-capped chickadee (Poecile atricapillus)

Most temperate songbird species sing seasonally, and the brain areas involved in producing song (the song system) vary in size alongside the changes in behavior. Black-capped chickadees (Poecile atricapillus) also sing seasonally, and we find that there are changes in the stereotypy and the length of the fee-bee song from the nonbreeding to the breeding season. Yet despite these changes, we fail to find any evidence of seasonal changes in the song system. The song system of males is larger than that of females, as is typical in songbirds, but the ratio between the sexes is small compared to other species. We suggest three hypotheses to explain our failure to find seasonal variation in the chickadee song system.     

A greedier approach for finding tag SNPs

MOTIVATION: Recent studies have shown that a small subset of Single Nucleotide Polymorphisms (SNPs) (called tag SNPs) is sufficient to capture the haplotype patterns in a high linkage disequilibrium region. To find the minimum set of tag SNPs, exact algorithms for finding the optimal solution could take exponential time. On the other hand, approximation algorithms are more efficient but may fail to find the optimal solution. RESULTS: We propose a hybrid method that combines the ideas of the branch-and-bound method and the greedy algorithm. This method explores larger solution space to obtain a better solution than a traditional greedy algorithm. It also allows the user to adjust the efficiency of the program and quality of solutions. This algorithm has been implemented and tested on a variety of simulated and biological data. The experimental results indicate that our program can find better solutions than previous methods. This approach is quite general since it can be used to adapt other greedy algorithms to solve their corresponding problems. AVAILABILITY: The program is available upon request.     

Text-derived concept profiles support assessment of DNA microarray data for acute myeloid leukemia and for androgen receptor stimulation

Background  

High-throughput experiments, such as with DNA microarrays, typically result in hundreds of genes potentially relevant to the process under study, rendering the interpretation of these experiments problematic. Here, we propose and evaluate an approach to find functional associations between large numbers of genes and other biomedical concepts from free-text literature. For each gene, a profile of related concepts is constructed that summarizes the context in which the gene is mentioned in literature. We assign a weight to each concept in the profile based on a likelihood ratio measure. Gene concept profiles can then be clustered to find related genes and other concepts.     

Stochastic effects in intercellular calcium spiking in hepatocytes

We carry out a Monte Carlo simulation of stochastic effects for two models of intercellular calcium wave propagation in rat hepatocytes. Both models involve gap junction diffusion by a second messenger. We find that, in general, the stochastic effects improve agreement with experiment, for a reasonable choice of model parameters. Both stochastic models exhibit baseline fluctuations and variations in the peak heights of Ca(2+). In addition, we find for one model that there is a distribution of latency times, rather than a single latency time, with a distribution width which is comparable to the experimental observation of spike widths. We also find for the other model with low gap junction diffusion that it is possible for cell multiplets to oscillate independently initially, but to subsequently become synchronized.     

Variation in the volume of zebra finch song control nuclei is heritable: developmental and evolutionary implications.

In many songbird species, females prefer males that sing a larger repertoire of syllables. Males with more elaborate songs have a larger high vocal centre (HVC) nucleus, the highest structure in the song production pathway. HVC size is thus a potential target of sexual selection. Here we provide evidence that the size of the HVC and other song production nuclei are heritable across individual males within a species. In contrast, we find that heritabilities of other nuclei in a song-learning pathway are lower, suggesting that variation in the sizes of these structures is more closely tied to developmental and environmental differences between individuals. We find that evolvability, a statistical measure that predicts response to selection, is higher for the HVC and its target for song production, the robustus archistriatalis (RA), than for all other brain volumes measured. This suggests that selection based on the functions of these two structures would result in rapid major shifts in their anatomy. We also show that the size of each song control nucleus is significantly correlated with the song related nuclei to which it is monosynaptically connected. Finally, we find that the volume of the telencephalon is larger in males than in females. These findings begin to join theoretical analyses of the role of female choice in the evolution of bird song to neurobiological mechanisms by which the evolutionary changes in behaviour are expressed.     

Transmission-virulence trade-offs in vector-borne diseases

Though it is commonly supposed that there is a trade-off between virulence and transmission, there is little data and little insight into what it should look like. Here, we consider the specific case of vector-borne parasites (inspired by human malaria) and analyse an embedded model to understand how specific life-cycle aspects may affect this trade-off. First, we find that, for such parasites, the transmission function may have an S-shape. Second, we find that the trade-off obtained for vector-borne parasites is less sensitive to parameter variations than the trade-off obtained for directly transmitted parasites. Third, we find that other parasite traits, such as the conversion from replicative to infective stages, could have important epidemiological implications. Finally, we compare the effect of treatments targeting either the asexual or the sexual parasite life-stage.     

Height and subjective well-being in Italy

Using an Italian survey, we investigate the effect of height on individual happiness. We find that a large part of the effect of height on well-being is driven by a positive correlation between height and economic and health conditions. However, for young men the effect of height on happiness persists even after controlling for these variables, implying that height is associated with some psycho-social direct effects on well-being. Consistent with this hypothesis, we find that men care not only about their own height but also about the height of others in their reference group. Well-being is greater for individuals who are taller than other men in their reference group. Results are robust to different definitions of reference group and controlling for a number of other reference group characteristics.     

Mitochondrial DNA variation in Drosophila pseudoobscura and related species in Pacific northwest populations

We have analysed mitochondrial DNA (mtDNA) from Pacific Northwest populations of Drosophila pseudoobscura, D. persimilis, and D. miranda using six restriction enzymes. We find that HpaII restriction sites are hypervariable compared to the other enzymes used. This hypervariability allows construction of a maximum parsimony map linking each mtDNA genotype. Small insertions, possibly tandem duplications, appear to have arisen concomitantly with, or subsequent to, speciation events, perhaps within the A + T rich region. Convergence of mtDNA genotypes is also evident. Unlike findings for other populations of these species, we find little evidence of mitochondrial introgression between D. pseudoobscura and D. persimilis, despite their ability to produce fertile hybrid females.     

Effect of group organization on the performance of cooperative processes

Problem-solving competence at group level is influenced by the structure of the social networks and so it may shed light on the organization patterns of gregarious animals. Here we use an agent-based model to investigate whether the ubiquity of hierarchical networks in nature could be explained as the result of a selection pressure favoring problem-solving efficiency. The task of the agents is to find the global maxima of NK fitness landscapes and the agents cooperate by broadcasting messages informing on their fitness to the group. This information is then used to imitate, with a certain probability, the fittest agent in their influence networks. The performance of the group is measured by the time required to find the global maximum. For rugged landscapes, we find that the modular organization of the hierarchical network with its high degree of clustering eases the escape from the local maxima, resulting in a superior performance as compared with the scale-free and the random networks. The optimal performance in a rugged landscape is achieved by letting the main hub to be only slightly more propense to imitate the other agents than vice versa. The performance is greatly harmed when the main hub carries out the search independently of the rest of the group as well as when it compulsively imitates the other agents.     

Fusion of influenza to liposomes is not inhibited by aliphatic primary alcohols

Reports of the antiviral activity of aliphatic alcohols led us to investigate the effects of aliphatic alcohols, from 10 to 20 carbons in length, on the phase transition behaviour of model phospholipids and on the fusion of influenza to liposomes. Contrary to the effects of many other antiviral agents, we find that alcohols are potent promoters of the inverted hexagonal phase. However, we also find that aliphatic alcohols have little effect on influenza fusion to liposomes. Eicosanol is the only aliphatic alcohol tested which substantially increases in fusion of influenza virus. We also find that long chain alcohols display multi-component bilayer to hexagonal phase transitions at higher mole fractions. This suggests that eicosanol may be facilitating fusion by creating defects between alcohol-rich and alcohol-poor regions of the lipid bilayer.     

Failure to detect seasonal changes in the song system nuclei of the black‐capped chickadee (Poecile atricapillus)

Most temperate songbird species sing seasonally, and the brain areas involved in producing song (the song system) vary in size alongside the changes in behavior. Black‐capped chickadees (Poecile atricapillus) also sing seasonally, and we find that there are changes in the stereotypy and the length of the fee‐bee song from the nonbreeding to the breeding season. Yet despite these changes, we fail to find any evidence of seasonal changes in the song system. The song system of males is larger than that of females, as is typical in songbirds, but the ratio between the sexes is small compared to other species. We suggest three hypotheses to explain our failure to find seasonal variation in the chickadee song system. © 2006 Wiley Periodicals, Inc. J Neurobiol, 2006     

Somatic excision of the Mu1 transposable element of maize.

The Mu transposons of the Robertsons's Mutator transposable element system in maize are unusual in many respects, when compared to the other known plant transposon systems. The excision of these elements occurs late in somatic tissues and very rarely in the germ line. Unlike the other plant transposons, there is no experimental evidence directly linking Mu element excision and integration. We have analyzed the excision products generated by a Mu1 transposon inserted into the bronze 1 locus of maize. We find that the excision products or 'footprints' left by the Mu1 element resemble those of the other plant transposable elements, rather than those of the animal transposable element systems. We also find some novel types of footprints resembling recombinational events. We suggest that the Mu1 element can promote intrachromosomal crossovers and conversions near its site of insertion, and that this may be another mechanism by which transposons can accelerate the evolution of genomes.     

Translation efficiency in humans: tissue specificity,global optimization and differences between developmental stages

Various studies in unicellular and multicellular organisms have shown that codon bias plays a significant role in translation efficiency (TE) by co-adaptation to the tRNA pool. Yet, in humans and other mammals the role of codon bias is still an open question, with contradictory results from different studies. Here we address this question, performing a large-scale tissue-specific analysis of TE in humans, using the tRNA Adaptation Index (tAI) as a direct measure for TE. We find tAI to significantly correlate with expression levels both in tissue-specific and in global expression measures, testifying to the TE of human tissues. Interestingly, we find significantly higher correlations in adult tissues as opposed to fetal tissues, suggesting that the tRNA pool is more adjusted to the adult period. Optimization based analysis suggests that the tRNA pool—codon bias co-adaptation is globally (and not tissue-specific) driven. Additionally, we find that tAI correlates with several measures related to the protein functionally importance, including gene essentiality. Using inferred tissue-specific tRNA pools lead to similar results and shows that tissue-specific genes are more adapted to their tRNA pool than other genes and that related sets of functional gene groups are translated efficiently in each tissue. Similar results are obtained for other mammals. Taken together, these results demonstrate the role of codon bias in TE in humans, and pave the way for future studies of tissue-specific TE in multicellular organisms.     

Evaluating Interactions of Forest Conservation Policies on Avoided Deforestation

We estimate the effects on deforestation that have resulted from policy interactions between parks and payments and between park buffers and payments in Costa Rica between 2000 and 2005. We show that the characteristics of the areas where protected and unprotected lands are located differ significantly. Additionally, we find that land characteristics of each of the policies and of the places where they interact also differ significantly. To adequately estimate the effects of the policies and their interactions, we use matching methods. Matching is implemented not only to define adequate control groups, as in previous research, but also to define those groups of locations under the influence of policies that are comparable to each other. We find that it is more effective to locate parks and payments away from each other, rather than in the same location or near each other. The high levels of enforcement inside both parks and lands with payments, and the presence of conservation spillovers that reduce deforestation near parks, significantly reduce the potential impact of combining these two policies.     

Reverse Engineering the Neuroblastoma Regulatory Network Uncovers MAX as One of the Master Regulators of Tumor Progression

Neuroblastoma is the most common extracranial tumor and a major cause of infant cancer mortality worldwide. Despite its importance, little is known about its molecular mechanisms. A striking feature of this tumor is its clinical heterogeneity. Possible outcomes range from aggressive invasion to other tissues, causing patient death, to spontaneous disease regression or differentiation into benign ganglioneuromas. Several efforts have been made in order to find tumor progression markers. In this work, we have reconstructed the neuroblastoma regulatory network using an information-theoretic approach in order to find genes involved in tumor progression and that could be used as outcome predictors or as therapeutic targets. We have queried the reconstructed neuroblastoma regulatory network using an aggressive neuroblastoma metastasis gene signature in order to find its master regulators (MRs). MRs expression profiles were then investigated in other neuroblastoma datasets so as to detect possible clinical significance. Our analysis pointed MAX as one of the MRs of neuroblastoma progression. We have found that higher MAX expression correlated with favorable patient outcomes. We have also found that MAX expression and protein levels were increased during neuroblastoma SH-SY5Y cells differentiation. We propose that MAX is involved in neuroblastoma progression, possibly increasing cell differentiation by means of regulating the availability of MYC:MAX heterodimers. This mechanism is consistent with the results found in our SH-SY5Y differentiation protocol, suggesting that MAX has a more central role in these cells differentiation than previously reported. Overexpression of MAX has been identified as anti-tumorigenic in other works, but, to our knowledge, this is the first time that the link between the expression of this gene and malignancy was verified under physiological conditions.