http://www.biology-direct.com The latest research articles published by Biology Direct 2012-05-08T00:00:00Z Background: The dynamics of viral infections have been studied extensively in a variety of settings, both experimentally and with mathematical models. The majori-ty of mathematical models assumes that only one virus can infect a given cell at a time. It is, however, clear that especially in the context of high viral load, cells can become infected with multiple copies of a virus, a process called coinfection. This has been best demonstrated experimentally for human immunodeficiency virus (HIV), although it is thought to be equally relevant for a number of other viral infections. In a previously explored mathematical model, the viral output from an infected cell does not depend on the number of viruses that reside in the cell, i.e. viral replication is limited by cellular rather than viral factors. In this case, basic virus dynamics properties are not altered by coinfection. Results: Here, we explore the alternative assumption that multiply infected cells are characterized by an increased burst size and find that this can fundamentally alter model predictions. Under this scenario, establishment of infection may not be solely determined by the basic reproductive ratio of the virus, but can depend on the initial virus load. Upon infection, the virus population need not follow straight exponential growth. Instead, the exponential rate of growth can increase over time as virus load becomes larger. Moreover, the model suggests that the ability of anti-viral drugs to suppress the virus population can depend on the virus load upon initiation of therapy. This is because more coinfected cells, which produce more virus, are present at higher virus loads. Hence, the degree of drug resistance is not only determined by the viral genotype, but also by the prevalence of coinfected cells. Conclusions: Our work shows how an increased burst size in multiply infected cells can alter basic infection dynamics. This forms the basis for future experimental testing of model assumptions and predictions that can distinguish between the different scenarios. http://www.biology-direct.com/content/7/1/16 Kara Cummings David Levy Dominik Wodarz Biology Direct 2012, null:16 2012-05-08T00:00:00Z doi:10.1186/1745-6150-7-16 /content/figures/1745-6150-7-16-toc.gif Biology Direct 1745-6150 ${item.volume} 16 2012-05-08T00:00:00Z PDF MicroRNAs (miRNAs) are endogenous small non-coding RNAs of about 20-24 nt, known to play key roles in post-transcriptional gene regulation, that can be coded either by intergenic or intragenic loci. Intragenic (exonic and intronic) miRNAs can exert a role in the transcriptional regulation and RNA processing of their host gene. Moreover, the possibility that the biogenesis of exonic miRNAs could destabilize the corresponding protein-coding transcript and reduce protein synthesis makes their characterization very intriguing and suggests a possible novel mechanism of post-transcriptional regulation of gene expression.This work was designed to carry out the computational identification of putative exonic miRNAs in 30 plant species and the analysis of possible mechanisms involved in their regulation.The results obtained represent a useful starting point for future studies on the complex networks involved in microRNA-mediated gene regulation in plants. http://www.biology-direct.com/content/7/1/15 Moreno Colaiacovo Antonella Lamontanara Letizia Bernardo Renzo Alberici Cristina Crosatti Lorenzo Giusti Luigi Cattivelli Primetta Faccioli Biology Direct 2012, null:15 2012-05-08T00:00:00Z doi:10.1186/1745-6150-7-15 /content/figures/1745-6150-7-15-toc.gif Biology Direct 1745-6150 ${item.volume} 15 2012-05-08T00:00:00Z PDF Background: mtRF1 is a vertebrate mitochondrial protein with an unknown function that arose from a duplication of the mitochondrial release factor mtRF1a. To elucidate the function of mtRF1, we determined the positions that are conserved among mtRF1 sequences but that are different in their mtRF1a paralogs. We subsequently modeled the 3D structure of mtRF1a and mtRF1 bound to the ribosome, highlighting the structural implications of these differences to derive a hypothesis for the function of mtRF1. Results: Our model predicts, in agreement with the experimental data, that the 3D structure of mtRF1a allows it to recognize the stop codons UAA and UAG in the A-site of the ribosome. In contrast, we show that mtRF1 likely can only bind the ribosome when the A-site is devoid of mRNA. Furthermore, while mtRF1a will adopt its catalytic conformation, in which it functions as a peptidyl-tRNA hydrolase in the ribosome, only upon binding of a stop codon in the A-site, mtRF1 appears specifically adapted to assume this extended, peptidyl-tRNA hydrolyzing conformation in the absence of mRNA in the A-site. Conclusions: We predict that mtRF1 specifically recognizes ribosomes with an empty A-site and is able to function as a peptidyl-tRNA hydrolase in those situations. Stalled ribosomes with empty A-sites that still contain a tRNA bound to a peptide chain can result from the translation of truncated, stop-codon less mRNAs. We hypothesize that mtRF1 recycles such stalled ribosomes, performing a function that is analogous to that of tmRNA in bacteria. http://www.biology-direct.com/content/7/1/14 Martijn Huynen Isabel Duarte Zofia Chrzanowska-Lightowlers Sander Nabuurs Biology Direct 2012, null:14 2012-05-08T00:00:00Z doi:10.1186/1745-6150-7-14 Modeling the 3D structure of the human protein mtRF1 shows that it likely functions in recognizing and recycling stalled mitochondrial ribosomes. /content/figures/1745-6150-7-14-toc.gif Biology Direct 1745-6150 ${item.volume} 14 2012-05-08T00:00:00Z PDF Background: Viruses are known to be the most abundant organisms on earth, yet little is known about their collective origin and evolutionary history. With exceptionally high rates of genetic mutation and mosaicism, it is not currently possible to resolve deep evolutionary histories of the known major virus groups. Metagenomics offers a potential means of establishing a more comprehensive view of viral evolution as vast amounts of new sequence data becomes available for comparative analysis. Results: Bioinformatic analysis of viral metagenomic sequences derived from a hot, acidic lake revealed a circular, putatively single-stranded DNA virus encoding a major capsid protein similar to those found only in single-stranded RNA viruses. The presence and circular configuration of the complete virus genome was confirmed by inverse PCR amplification from native DNA extracted from lake sediment. The virus genome appears to be the result of a RNA-DNA recombination event between two ostensibly unrelated virus groups. Environmental sequence databases were examined for homologous genes arranged in similar configurations and three similar putative virus genomes from marine environments were identified. This result indicates the existence of a widespread but previously undetected group of viruses. Conclusions: This unique viral genome carries implications for theories of virus emergence and evolution, as no mechanism for interviral RNA-DNA recombination has yet been identified, and only scant evidence exists that genetic exchange occurs between such distinct virus lineages.ReviewersThis article was reviewed by EK, MK (nominated by PF) and AM. For the full reviews, please go to the Reviewers' comments section. http://www.biology-direct.com/content/7/1/13 Geoffrey Diemer Kenneth Stedman Biology Direct 2012, null:13 2012-04-19T00:00:00Z doi:10.1186/1745-6150-7-13 Hybrid viral genome discovered in extreme environment The discovery of a previously unknown viral genome, the apparent result of a recombination event between unrelated RNA and DNA viruses, has implications for theories of viral evolution. /content/figures/1745-6150-7-13-toc.gif Biology Direct 1745-6150 ${item.volume} 13 2012-04-19T00:00:00Z PDF Background: BLAST is a commonly-used software package for comparing a query sequence to a database of known sequences; in this study, we focus on protein sequences. Position-specific-iterated BLAST (PSI-BLAST) iteratively searches a protein sequence database, using the matches in round i to construct a position-specific score matrix (PSSM) for searching the database in round i + 1. Biegert and Soding developed Context-sensitive BLAST (CS-BLAST), which combines information from searching the sequence database with information derived from a library of short protein profiles to achieve better homology detection than PSI-BLAST, which builds its PSSMs from scratch. Results: We describe a new method, called domain enhanced lookup time accelerated BLAST (DELTA-BLAST), which searches a database of pre-constructed PSSMs before searching a protein-sequence database, to yield better homology detection. For its PSSMs, DELTA-BLAST employs a subset of NCBI's Conserved Domain Database (CDD). On a test set derived from ASTRAL, with one round of searching, DELTA-BLAST achieves a ROC_5000 of 0.270 vs. 0.116 for CS-BLAST. The performance advantage diminishes in iterated searches, but DELTA-BLAST continues to achieve better ROC scores than CS-BLAST. Conclusions: DELTA-BLAST is a useful program for the detection of remote protein homologs. It is available under the "Protein BLAST" link at http://blast.ncbi.nlm.nih.gov.Reviewers: This article was reviewed by Arcady Mushegian, Nick V. Grishin, and Frank Eisenhaber. http://www.biology-direct.com/content/7/1/12 Grzegorz Boratyn Alejandro Schaffer Richa Agarwala Stephen Altschul David Lipman Thomas Madden Biology Direct 2012, null:12 2012-04-17T00:00:00Z doi:10.1186/1745-6150-7-12 Domain enhanced lookup time accelerated BLAST DELTA-BLAST is a new BLAST alignment tool for sensitive protein searches that uses conserved domain models to construct a position specific scoring matrix. /content/figures/1745-6150-7-12-toc.gif Biology Direct 1745-6150 ${item.volume} 12 2012-04-17T00:00:00Z PDF Evolution of exon-intron structure of eukaryotic genes has been a matter of long-standing, intensive debate. The introns-early concept, later rebranded 'introns first' held that protein-coding genes were interrupted by numerous introns even at the earliest stages of life's evolution and that introns played a major role in the origin of proteins by facilitating recombination of sequences coding for small protein/peptide modules. The introns-late concept held that introns emerged only in eukaryotes and new introns have been accumulating continuously throughout eukaryotic evolution. Analysis of orthologous genes from completely sequenced eukaryotic genomes revealed numerous shared intron positions in orthologous genes from animals and plants and even between animals, plants and protists, suggesting that many ancestral introns have persisted since the last eukaryotic common ancestor (LECA). Reconstructions of intron gain and loss using the growing collection of genomes of diverse eukaryotes and increasingly advanced probabilistic models convincingly show that the LECA and the ancestors of each eukaryotic supergroup had intron-rich genes, with intron densities comparable to those in the most intron-rich modern genomes such as those of vertebrates. The subsequent evolution in most lineages of eukaryotes involved primarily loss of introns, with only a few episodes of substantial intron gain that might have accompanied major evolutionary innovations such as the origin of metazoa. The original invasion of self-splicing Group II introns, presumably originating from the mitochondrial endosymbiont, into the genome of the emerging eukaryote might have been a key factor of eukaryogenesis that in particular triggered the origin of endomembranes and the nucleus. Conversely, splicing errors gave rise to alternative splicing, a major contribution to the biological complexity of multicellular eukaryotes. There is no indication that any prokaryote has ever possessed a spliceosome or introns in protein-coding genes, other than relatively rare mobile self-splicing introns. Thus, the introns-first scenario is not supported by any evidence but exon-intron structure of protein-coding genes appears to have evolved concomitantly with the eukaryotic cell, and introns were a major factor of evolution throughout the history of eukaryotes. This article was reviewed by I. King Jordan, Manuel Irimia (nominated by Anthony Poole), Tobias Mourier (nominated by Anthony Poole), and Fyodor Kondrashov. For the complete reports, see the Reviewers' Reports section. http://www.biology-direct.com/content/7/1/11 Igor Rogozin Liran Carmel Miklos Csuros Eugene Koonin Biology Direct 2012, null:11 2012-04-16T00:00:00Z doi:10.1186/1745-6150-7-11 /content/figures/1745-6150-7-11-toc.gif Biology Direct 1745-6150 ${item.volume} 11 2012-04-16T00:00:00Z PDF Tubulins are a family of GTPases that are key components of the cytoskeleton in all eukaryotes and are distantly related to the FtsZ GTPase that is involved in cell division in most bacteria and many archaea. Among prokaryotes, bona fide tubulins have been identified only in bacteria of the genus Prosthecobacter. These bacterial tubulin genes appear to have been horizontally transferred from eukaryotes. Here we describe tubulins encoded in the genomes of thaumarchaeota of the genus Nitrosoarchaeum that we denote artubulins Phylogenetic analysis results are compatible with the origin of eukaryotic tubulins from artubulins. These findings expand the emerging picture of the origin of key components of eukaryotic functional systems from ancestral forms that are scattered among the extant archaea.ReviewersThis article was reviewed by Gáspár Jékely and J. Peter Gogarten. http://www.biology-direct.com/content/7/1/10 Natalya Yutin Eugene Koonin Biology Direct 2012, null:10 2012-03-29T00:00:00Z doi:10.1186/1745-6150-7-10 Probable ancestors of eukaryotic tubulins, denoted artubulins, were discovered in two genomes of thaumarchaeota of the genus Nitrosoarchaeum. /content/figures/1745-6150-7-10-toc.gif Biology Direct 1745-6150 ${item.volume} 10 2012-03-29T00:00:00Z XML Background: Injuries to articular cartilage result in the development of lesions that form on the surface of the cartilage. Such lesions are associated with articular cartilage degeneration and osteoarthritis. The typical injury response often causes collateral damage, primarily an effect of inflammation, which results in the spread of lesions beyond the region where the initial injury occurs.Results and discussionWe present a minimal mathematical model based on known mechanisms to investigate the spread and abatement of such lesions. The first case corresponds to the parameter values listed in Table 1, while the second case has parameter values as in Table 2. In particular we represent the "balancing act" between pro-inflammatory and anti-inflammatory cytokines that is hypothesized to be a principal mechanism in the expansion properties of cartilage damage during the typical injury response. We present preliminary results of in vitro studies that confirm the anti-inflammatory activities of the cytokine erythropoietin (EPO). We assume that the diffusion of cytokines determine the spatial behavior of injury response and lesion expansion so that a reaction diffusion system involving chemical species and chondrocyte cell state population densities is a natural way to represent cartilage injury response. We present computational results using the mathematical model showing that our representation is successful in capturing much of the interesting spatial behavior of injury associated lesion development and abatement in articular cartilage. Further, we discuss the use of this model to study the possibility of using EPO as a therapy for reducing the amount of inflammation induced collateral damage to cartilage during the typical injury response.Table 1Model Parameter Values for Results in Figure 5Table of Parameter Values Corresponding to Simulations in Figure 5ParameterValueUnitsReasonD R0.1c m 2 dayDetermined from 13D M0.05c m 2 dayDetermined from 13D F0.05c m 2 dayDetermined from 13D P0.005c m 2 dayDetermined from 13δ R0.011 dayApproximatedδ M0.61 dayApproximatedδ F0.61 dayApproximatedδ P0.00871 dayApproximatedδ U0.00011 dayApproximatedσ R0.0001micromolar ⋅ c m 2 day ⋅ cellsApproximatedσ M0.00001micromolar ⋅ c m 2 day ⋅ cellsApproximatedσ F0.0001micromolar ⋅ c m 2 day ⋅ cellsApproximatedσ P0micromolar ⋅ c m 2 day ⋅ cellsCase with no anti-inflammatory responseΛ10micromolarApproximatedλ R10micromolarApproximatedλ M10micromolarApproximatedλ F10micromolarApproximatedλ P10micromolarApproximatedα01 dayCase with no anti-inflammatory responseβ 11001 dayApproximatedΒ 2501 dayApproximatedγ101 dayApproximatedν0.51 dayApproximatedμ S A11 dayApproximatedμ D N0.51 dayApproximatedτ 10.5daysTaken from 5τ 21daysTaken from 5Table 2Model Parameter Values for Results in Figure 6Table of Parameter Values Corresponding to Simulations in Figure 6ParameterValueUnitsReasonD R0.1c m 2 dayDetermined from 13D M0.05c m 2 dayDetermined from 13D F0.05c m 2 dayDetermined from 13DP0.005c m 2 dayDetermined from 13δ R0.011 dayApproximatedδ M0.61 dayApproximatedδ F0.61 dayApproximatedδ P0.00871 dayApproximatedδ U0.00011 dayApproximatedσ R0.0001micromolar ⋅ c m 2 day ⋅ cellsApproximatedσ M0.00001micromolar ⋅ c m 2 day ⋅ cellsApproximatedσ F0.0001micromolar ⋅ c m 2 day ⋅ cellsApproximatedσ P0.001micromolar ⋅ c m 2 day ⋅ cellsApproximatedΛ10micromolarApproximatedλ R10micromolarApproximatedλ M10micromolarApproximatedλ F10micromolarApproximatedλ P10micromolarApproximatedα101 dayApproximatedβ 11001 dayApproximatedβ 2501 dayApproximatedγ101 dayApproximatedν0.51 dayApproximatedμ S A11 dayApproximatedμ D N0.51 dayApproximatedτ 10.5daysTaken from 5τ 21daysTaken from 5 Conclusions: The mathematical model presented herein suggests that not only are anti-inflammatory cy-tokines, such as EPO necessary to prevent chondrocytes signaled by pro-inflammatory cytokines from entering apoptosis, they may also influence how chondrocytes respond to signaling by pro-inflammatory cytokines.ReviewersThis paper has been reviewed by Yang Kuang, James Faeder and Anna Marciniak-Czochra. http://www.biology-direct.com/content/7/1/9 Jason Graham Bruce Ayati Lei Ding Prem Ramakrishnan James Martin Biology Direct 2012, null:9 2012-02-21T00:00:00Z doi:10.1186/1745-6150-7-9 Graham et al. present a mathematical model that connects the biochemical interactions of cartilage cells with the spatial behavior observed in cartilage injury. /content/figures/1745-6150-7-9-toc.gif Biology Direct 1745-6150 ${item.volume} 9 2012-02-21T00:00:00Z XML Background: Evolution at a protein site can be characterized from two different perspectives, by its rate and by the breadth of the set of acceptable amino acids. Results: There is a weak positive correlation between rates and breadths of evolution, both across individual amino acid sites and across proteins. Conclusions: Rate and breadth are two distinct, and only weakly correlated, characteristics of protein evolution. The most likely explanation of their positive correlation is heterogeneity of selective constraint, such that less functionally important sites evolve faster and can accept more amino acids.ReviewersThis article was reviewed by Eugene V. Koonin, Arcady R. Mushegyan, and Eugene I. Shakhnovich. http://www.biology-direct.com/content/7/1/8 Sergey Naumenko Alexey Kondrashov Biology Direct 2012, null:8 2012-02-15T00:00:00Z doi:10.1186/1745-6150-7-8 /content/figures/1745-6150-7-8-toc.gif Biology Direct 1745-6150 ${item.volume} 8 2012-02-15T00:00:00Z XML Background: In eukaryotes, the CMG (CDC45, MCM, GINS) complex containing the replicative helicase MCM is a key player in DNA replication. Archaeal homologs of the eukaryotic MCM and GINS proteins have been identified but until recently no homolog of the CDC45 protein was known. Two recent developments, namely the discovery of archaeal GINS-associated nuclease (GAN) that belongs to the RecJ family of the DHH hydrolase superfamily and the demonstration of homology between the DHH domains of CDC45 and RecJ, show that at least some Archaea possess a full complement of homologs of the CMG complex subunits. Here we present the results of in-depth phylogenomic analysis of RecJ homologs in archaea. Results: We confirm and extend the recent hypothesis that CDC45 is the eukaryotic ortholog of the bacterial and archaeal RecJ family nucleases. At least one RecJ homolog was identified in all sequenced archaeal genomes, with the single exception of Caldivirga maquilingensis. These proteins include previously unnoticed remote RecJ homologs with inactivated DHH domain in Thermoproteales. Combined with phylogenetic tree reconstruction of diverse eukaryotic, archaeal and bacterial DHH subfamilies, this analysis yields a complex scenario of RecJ family evolution in Archaea which includes independent inactivation of the nuclease domain in Crenarchaeota and Halobacteria, and loss of this domain in Methanococcales. Conclusions: The archaeal complex of a CDC45/RecJ homolog, MCM and GINS is homologous and most likely functionally analogous to the eukaryotic CMG complex, and appears to be a key component of the DNA replication machinery in all Archaea. It is inferred that the last common archaeo-eukaryotic ancestor encoded a CMG complex that contained an active nuclease of the RecJ family. The inactivated RecJ homologs in several archaeal lineages most likely are dedicated structural components of replication complexes.ReviewersThis article was reviewed by Prof. Patrick Forterre, Dr. Stephen John Aves (nominated by Dr. Purificacion Lopez-Garcia) and Prof. Martijn Huynen.For the full reviews, see the Reviewers' Comments section. http://www.biology-direct.com/content/7/1/7 Kira Makarova Eugene Koonin Zvi Kelman Biology Direct 2012, null:7 2012-02-13T00:00:00Z doi:10.1186/1745-6150-7-7 Comparative genomic analysis reveals diverged orthologs of eukaryotic CDC45 protein and bacterial RecJ nuclease in nearly all archaeal genomes; the CMG complex is conserved in both archaea and eukaryotes, and appears to be an essential component of the ancestral DNA replication machinery. /content/figures/1745-6150-7-7-toc.gif Biology Direct 1745-6150 ${item.volume} 7 2012-02-13T00:00:00Z XML