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1.  Reviewer acknowledgement 
Biology Direct  2015;10:7.
Contributing reviewers
The editors of Biology Direct would like to thank all the reviewers who have contributed to the journal in Volume 9 (2014).
doi:10.1186/s13062-015-0038-9
PMCID: PMC4336480
2.  Dynamics of social network structure for Alzheimer and Lymphoma scientific communities 
Biology Direct  2015;10:6.
Abstract
It is generally assumed that sociology affects scientific progress but specific examples of this assumption are hard to find. We examined this hypothesis by comparing the social network structure and its dynamics over the last 16 years, for two common human diseases; Alzheimer’s disease, for which there has been very little therapeutic progress, and Lymphoma, were there has been significant therapeutic progress. We found that the Alzheimer’s research community is more interlinked (‘dense’) and more ‘cliquish’ than that of Lymphoma and suggest that this could affect its scientific progress.
Reviewers
This article was reviewed by Vladimir Kuznetsov and Anthony Almudevar
doi:10.1186/s13062-015-0040-2
PMCID: PMC4335781
Alzheimer’s disease; Lymphoma; Social network
3.  Whole-genome assembly of Akkermansia muciniphila sequenced directly from human stool 
Biology Direct  2015;10:5.
Background
Alterations in gut microbiota composition under antibiotic pressure have been widely studied, revealing a restricted diversity of gut flora, including colonization by organisms such as Enterococci, while their impact on bacterial load is variable. High-level colonization by Akkermansia muciniphila, ranging from 39% to 84% of the total bacterial population, has been recently reported in two patients being treated with broad-spectrum antibiotics, although attempts to cultivate this microorganism have been unsuccessful.
Results
Here, we propose an original approach of genome sequencing for Akkermansia muciniphila directly from the stool sample collected from one of these patients. We performed and assembly using metagenomic data obtained from the stool sample. We used a mapping method consisting of aligning metagenomic sequencing reads against the reference genome of the Akkermansia muciniphila MucT strain, and a De novo assembly to support this mapping method. We obtained draft genome of the Akkermansia muciniphila strain Urmite with only 56 gaps. The absence of particular metabolic requirement as possible explanation of our inability to culture this microorganism, suggests that the bacterium was dead before the inoculation of the stool sample. Additional antibiotic resistance genes were found following comparison with the reference genome, providing some clues pertaining to its survival and colonization in the gut of a patient treated with broad-spectrum antimicrobial agents. However, no gene coding for imipenem resistance was detected, although this antibiotic was a part of the patient’s antibiotic regimen.
Conclusions
This work highlights the potential of metagenomics to facilitate the assembly of genomes directly from human stool.
Reviewers
This article was reviewed by Eric Bapteste, William Martin and Vivek Anantharaman.
Electronic supplementary material
The online version of this article (doi:10.1186/s13062-015-0041-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s13062-015-0041-1
PMCID: PMC4333879
Akkermansia muciniphila; Genome; Gut microbiota; Metagenomics; Antibiotics
4.  “Off-Spotter”: very fast and exhaustive enumeration of genomic lookalikes for designing CRISPR/Cas guide RNAs 
Biology Direct  2015;10:4.
Background
CRISPR/Cas (Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR associated nucleases) is a powerful component of the prokaryotic immune system that has been adapted for targeted genetic engineering in higher organisms. A key element of CRISPR/Cas is the “guide” RNA (gRNA) that is ~20 nucleotides (nts) in length and designed to be complementary to the intended target site. An integral requirement of the CRISPR/Cas system is that the target site be followed by a protospacer adjacent motif (PAM). Care needs to be exercised during gRNA design to avoid unintended (“off-target”) interactions.
Results
We designed and implemented the Off-Spotter algorithm to assist with the design of optimal gRNAs. When presented with a candidate gRNA sequence and a PAM, Off-Spotter quickly and exhaustively identifies all genomic sites that satisfy the PAM constraint and are identical or nearly-identical to the provided gRNA. Off-Spotter achieves its extreme performance through purely algorithmic means and not through hardware accelerators such as graphical processing units (GPUs). Off-Spotter also allows the user to identify on-the-fly how many and which nucleotides of the gRNA comprise the “seed”. Off-Spotter’s output includes a histogram showing the number of potential off-targets as a function of the number of mismatches. The output also includes for each potential off-target the site’s genomic location, a human genome browser hyperlink to the corresponding location, genomic annotation in the vicinity of the off-target, GC content, etc.
Conclusion
Off-Spotter is very fast and flexible and can help in the design of optimal gRNAs by providing several PAM choices, a run-time definition of the seed and of the allowed number of mismatches, and a flexible output interface that allows sorting of the results, optional viewing/hiding of columns, etc. A key element of Off-Spotter is that it does not have a rigid definition of the seed: instead, the user can declare both the seed’s location and extent on-the-fly. We expect that this flexibility in combination with Off-Spotter’s speed and richly annotated output will enable experimenters to interactively and quickly explore different scenarios and gRNA possibilities.
Reviewed
This article was reviewed by Dr Eugene Koonin and Dr Frank Eisenhaber.
Electronic supplementary material
The online version of this article (doi:10.1186/s13062-015-0035-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s13062-015-0035-z
PMCID: PMC4326336  PMID: 25630343
CRISPR; Off-targets; Cas endonucleases; Cas9; Guide RNAs; gRNAs; Indexing; Hashing
5.  The microbiome mutiny hypothesis: can our microbiome turn against us when we are old or seriously ill? 
Biology Direct  2015;10:3.
Background
The symbiotic organisms of the healthy microbiome tend to be harmless or even beneficial for the host; however, some symbionts are able to adjust their virulence in response to external stimuli. Evolutionary theory suggests that optimal virulence might increase if the mortality of the host (from unrelated causes) increases.
Presentation of the hypothesis
We hypothesize that microorganisms of the human microbiome may be capable of a coordinated phenotypic switch to higher virulence (“microbiome mutiny”) in old or seriously ill people, to optimize their transmission under the conditions of increased background mortality. This proposed virulence shift might contribute to the death of old or seriously ill people even in the absence of apparent disease.
Testing the hypothesis
Testable predictions of the hypothesis include increased expression of virulence factors in isolates of the same species of the microbiome obtained from ailing/old versus healthy/young individuals, and the existence of microbial mechanisms to assess the general condition (background mortality) of the host. Such tests are going to be important to distinguish the cases of “microbiome mutiny” from the situation where opportunistic infections or increased effective virulence arise from relaxed immune control in ailing or old individuals in the absence of changes in the symbionts/pathogens.
Implications of the hypothesis
Elucidating this potential mechanism might open up new possibilities for the clinical management of age related health issues and critical injuries or disease. Targeted prophylaxis against the microbes capable of virulence shifts could break the harmful feedback loop between deteriorating health and the “mutiny” of the microbiome.
Reviewers
This article was reviewed by Eugene V Koonin, Neil Greenspan and Michael Gilchrist.
doi:10.1186/s13062-014-0034-5
PMCID: PMC4302444  PMID: 25585878
Evolutionary medicine; Facultative virulence; Microbiome; Host-pathogen communication; Pathogenesis
6.  Genome-wide association study for posthitis in the free-living population of European bison (Bison bonasus) 
Biology Direct  2015;10:2.
Background
About 5–6% of the European bison (Bison bonasus) males are affected by posthitis (necrotic inflammation of the prepuce) and die in the wild forest. Despite many years of study, pathogenesis of this disease has not yet been determined. The main aim of the study was to find SNP markers significantly associated with the incidence of posthitis and mine the genome for candidate genes potentially involved in the development of the disease.
Results
It was shown that relatively small number of SNPs effects reached genome-wide significance after false discovery rate (FDR) correction. Among 25 significant markers, the highest effects were found for two SNPs (rs110456748 and rs136792896) located at the distance of 23846 bp and 37742 bp, respectively, from OR10A3 gene (olfactory receptor genes), known to be involved in atopic dermatitis in humans. It was also observed that five other significant SNP markers were located in the proximity of candidate genes involved in severe diseases of skin tissue and cancer/tumour development of epithelial or testicular germ cells, which suggest their potential participation in the posthitis. The 25 investigated SNPs showed marked differences in allelic and genotypic frequencies between the healthy and affected bison groups.
Conclusions
The 2 Mb region of the BTA15 chromosome is involved in genetic background of posthitis and should be closer examined to find causal mutations helpful in better understanding of the disease ethology and to control its incidence in the future.
Reviewers
This article was reviewed by Prof. Lev Klebanov and Dr. Fyodor Kondrashov.
doi:10.1186/s13062-014-0033-6
PMCID: PMC4302601  PMID: 25585689
Bison; Posthitis; GWAS; Illumina BovineHD 777K
7.  A new ensemble coevolution system for detecting HIV-1 protein coevolution 
Biology Direct  2015;10:1.
Background
A key challenge in the field of HIV-1 protein evolution is the identification of coevolving amino acids at the molecular level. In the past decades, many sequence-based methods have been designed to detect position-specific coevolution within and between different proteins. However, an ensemble coevolution system that integrates different methods to improve the detection of HIV-1 protein coevolution has not been developed.
Results
We integrated 27 sequence-based prediction methods published between 2004 and 2013 into an ensemble coevolution system. This system allowed combinations of different sequence-based methods for coevolution predictions. Using HIV-1 protein structures and experimental data, we evaluated the performance of individual and combined sequence-based methods in the prediction of HIV-1 intra- and inter-protein coevolution. We showed that sequence-based methods clustered according to their methodology, and a combination of four methods outperformed any of the 27 individual methods. This four-method combination estimated that HIV-1 intra-protein coevolving positions were mainly located in functional domains and physically contacted with each other in the protein tertiary structures. In the analysis of HIV-1 inter-protein coevolving positions between Gag and protease, protease drug resistance positions near the active site mostly coevolved with Gag cleavage positions (V128, S373-T375, A431, F448-P453) and Gag C-terminal positions (S489-Q500) under selective pressure of protease inhibitors.
Conclusions
This study presents a new ensemble coevolution system which detects position-specific coevolution using combinations of 27 different sequence-based methods. Our findings highlight key coevolving residues within HIV-1 structural proteins and between Gag and protease, shedding light on HIV-1 intra- and inter-protein coevolution.
Reviewers
This article was reviewed by Dr. Zoltán Gáspári.
Electronic supplementary material
The online version of this article (doi:10.1186/s13062-014-0031-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s13062-014-0031-8
PMCID: PMC4332441  PMID: 25564011
HIV-1; Protein coevolution; Gag; Protease; Ensemble coevolution system; Sequence-based method
8.  Once upon a time the cell membranes: 175 years of cell boundary research 
Biology Direct  2014;9:32.
Abstract
All modern cells are bounded by cell membranes best described by the fluid mosaic model. This statement is so widely accepted by biologists that little attention is generally given to the theoretical importance of cell membranes in describing the cell. This has not always been the case. When the Cell Theory was first formulated in the XIXth century, almost nothing was known about the cell membranes. It was not until well into the XXth century that the existence of the plasma membrane was broadly accepted and, even then, the fluid mosaic model did not prevail until the 1970s. How were the cell boundaries considered between the articulation of the Cell Theory around 1839 and the formulation of the fluid mosaic model that has described the cell membranes since 1972? In this review I will summarize the major historical discoveries and theories that tackled the existence and structure of membranes and I will analyze how these theories impacted the understanding of the cell. Apart from its purely historical relevance, this account can provide a starting point for considering the theoretical significance of membranes to the definition of the cell and could have implications for research on early life.
Reviewers
This article was reviewed by Dr. Étienne Joly, Dr. Eugene V. Koonin and Dr. Armen Mulkidjanian.
doi:10.1186/s13062-014-0032-7
PMCID: PMC4304622  PMID: 25522740
Cell membrane discovery; Cell membrane structure; Cell Theory; History of Science; Cell definition; Origins of life; Early evolution; Cenancestor
9.  The fundamental tradeoff in genomes and proteomes of prokaryotes established by the genetic code, codon entropy, and physics of nucleic acids and proteins 
Biology Direct  2014;9(1):29.
Background
Mutations in nucleotide sequences provide a foundation for genetic variability, and selection is the driving force of the evolution and molecular adaptation. Despite considerable progress in the understanding of selective forces and their compositional determinants, the very nature of underlying mutational biases remains unclear.
Results
We explore here a fundamental tradeoff, which analytically describes mutual adjustment of the nucleotide and amino acid compositions and its possible effect on the mutational biases. The tradeoff is determined by the interplay between the genetic code, optimization of the codon entropy, and demands on the structure and stability of nucleic acids and proteins.
Conclusion
The tradeoff is the unifying property of all prokaryotes regardless of the differences in their phylogenies, life styles, and extreme environments. It underlies mutational biases characteristic for genomes with different nucleotide and amino acid compositions, providing foundation for evolution and adaptation.
Reviewers
This article was reviewed by Eugene Koonin, Michael Gromiha, and Alexander Schleiffer.
Electronic supplementary material
The online version of this article (doi:10.1186/s13062-014-0029-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s13062-014-0029-2
PMCID: PMC4273451  PMID: 25496919
Fundamental tradeoff; Genomes; Proteomes; Prokaryotes; Nucleic acids; Proteins; Structure; Stability; Evolution; Adaptation
10.  Genome-scale identification and characterization of moonlighting proteins 
Biology Direct  2014;9:30.
Background
Moonlighting proteins perform two or more cellular functions, which are selected based on various contexts including the cell type they are expressed, their oligomerization status, and the binding of different ligands at different sites. To understand overall landscape of their functional diversity, it is important to establish methods that can identify moonlighting proteins in a systematic fashion. Here, we have developed a computational framework to find moonlighting proteins on a genome scale and identified multiple proteomic characteristics of these proteins.
Results
First, we analyzed Gene Ontology (GO) annotations of known moonlighting proteins. We found that the GO annotations of moonlighting proteins can be clustered into multiple groups reflecting their diverse functions. Then, by considering the observed GO term separations, we identified 33 novel moonlighting proteins in Escherichia coli and confirmed them by literature review. Next, we analyzed moonlighting proteins in terms of protein-protein interaction, gene expression, phylogenetic profile, and genetic interaction networks. We found that moonlighting proteins physically interact with a higher number of distinct functional classes of proteins than non-moonlighting ones and also found that most of the physically interacting partners of moonlighting proteins share the latter’s primary functions. Interestingly, we also found that moonlighting proteins tend to interact with other moonlighting proteins. In terms of gene expression and phylogenetically related proteins, a weak trend was observed that moonlighting proteins interact with more functionally diverse proteins. Structural characteristics of moonlighting proteins, i.e. intrinsic disordered regions and ligand binding sites were also investigated.
Conclusion
Additional functions of moonlighting proteins are difficult to identify by experiments and these proteins also pose a significant challenge for computational function annotation. Our method enables identification of novel moonlighting proteins from current functional annotations in public databases. Moreover, we showed that potential moonlighting proteins without sufficient functional annotations can be identified by analyzing available omics-scale data. Our findings open up new possibilities for investigating the multi-functional nature of proteins at the systems level and for exploring the complex functional interplay of proteins in a cell.
Reviewers
This article was reviewed by Michael Galperin, Eugine Koonin, and Nick Grishin.
Electronic supplementary material
The online version of this article (doi:10.1186/s13062-014-0030-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s13062-014-0030-9
PMCID: PMC4307903  PMID: 25497125
Moonlighting protein; Multitasking; Function annotation; Genome; Omics data
11.  Mammalian Argonaute-DNA binding? 
Biology Direct  2014;10:27.
When a field shares the consensus that a particular phenomenon does NOT occur, this may reflect extensive experimental investigations with negative outcomes, or may represent the “common sense” position based on current knowledge and established ways of thinking. The current consensus of the RNA field is that eukaryotic Argonaute (Ago) proteins employ RNA guides and target other RNAs. The alternative -- that eukaryotic Ago has biologically important interactions with DNA in vivo – has not been seriously considered, in part because the only role contemplated for DNA was as a guide strand, and in part because it did not seem plausible that any natural source of suitable DNAs exists in eukaryotic cells. However, eukaryotic Argonaute domains bind DNA in the test tube, and several articles report that small inhibitory double-stranded DNAs do have the ability to silence target RNAs in a sequence-dependent (though poorly characterized) manner. A search of the literature identified potential DNA binding partners for Ago, including (among others) single-stranded DNAs residing in extracellular vesicles, and cytoplasmic satellite-repeat DNA fragments that are associated with the plasma membrane and transcribed by Pol II. It is interesting to note that both cytoplasmic and extracellular vesicle DNA are expressed at greatly elevated levels in cancer cells relative to normal cells. In such a pathological scenario, if not under normal conditions, there may be appreciable binding of Ago to DNA despite its lower affinity compared to RNA. If so, DNA might displace Ago from binding to its normal partners (miRNAs, siRNAs and other short ncRNAs), disrupting tightly controlled post-transcriptional gene silencing processes that are vital to correct functioning of a normal cell. The possible contribution to cancer pathogenesis is a strong motivator for further investigation of Ago-DNA binding. More generally, this case underscores the need for better informatics tools to allow investigators to analyze the state of a given scientific question at a high-level and to identify possible new research directions.
Reviewers: This article was reviewed by Eugene Koonin, Kira S. Makarova, Alexander Maxwell Burroughs (nominated by L Aravind), and Isidore Rigoutsos.
Open peer review: Reviewed by Eugene Koonin, Kira S. Makarova, Alexander Maxwell Burroughs (nominated by L Aravind), and Isidore Rigoutsos. For the full reviews, please go to the Reviewers’ comments section.
doi:10.1186/s13062-014-0027-4
PMCID: PMC4258305  PMID: 25472905
Consensus; Hypothesis assessment; Scientific discovery; DNA interference; Cytoplasmic DNA; RNA interference
12.  Molecular complementarity between simple, universal molecules and ions limited phenotype space in the precursors of cells 
Biology Direct  2014;10:28.
Background
Fundamental problems faced by the protocells and their modern descendants include how to go from one phenotypic state to another; escape from a basin of attraction in the space of phenotypes; reconcile conflicting growth and survival strategies (and thereby live on ‘the scales of equilibria’); and create a coherent, reproducible phenotype from a multitude of constituents.
Presentation of the hypothesis
The solutions to these problems are likely to be found with the organic and inorganic molecules and inorganic ions that constituted protocells, which we term SUMIs for Simple Universal Molecules and Ions. These SUMIs probably included polyphosphate (PolyP) as a source of energy and of phosphate; poly-(R)-3-hydroxybutyrate (PHB) as a source of carbon and as a transporter in association with PolyP; polyamines as a source of nitrogen; lipids as precursors of membranes; as well as peptides, nucleic acids, and calcium. Here, we explore the hypothesis that the direct interactions between PHB, PolyP, polyamines and lipids – modulated by calcium – played a central role in solving the fundamental problems faced by early and modern cells.
Testing the hypothesis
We review evidence that SUMIs (1) were abundant and available to protocells; (2) are widespread in modern cells; (3) interact with one another and other cellular constituents to create structures with new functions surprisingly similar to those of proteins and RNA; (4) are essential to creating coherent phenotypes in modern bacteria. SUMIs are therefore natural candidates for reducing the immensity of phenotype space and making the transition from a “primordial soup” to living cells.
Implications of the hypothesis
We discuss the relevance of the SUMIs and their interactions to the ideas of molecular complementarity, composomes (molecular aggregates with hereditary properties based on molecular complementarity), and a prebiotic ecology of co-evolving populations of composomes. In particular, we propose that SUMIs might limit the initial phenotype space of composomes in a coherent way. As examples, we propose that acidocalcisomes arose from interactions and self-selection among SUMIs and that the phosphorylation of proteins in modern cells had its origin in the covalent modification of proteins by PHB.
Reviewers
This article was reviewed by Doron Lancet and Kepa Ruiz-Mirazo.
doi:10.1186/s13062-014-0028-3
PMCID: PMC4264330  PMID: 25470982
Origin of life; Protein kinase; Hyperstructure; Network; Cation; Polymer; Complementarity; DNA; RNA
13.  Microbes on the edge of Occam’s razor 
Biology Direct  2014;10:25.
Abstract
Our body harbors hundreds of microbial species and contains many more bacterial than human cells. These microbes are not passive riders but rather a vital component of the organism. The human microbiota affects our health in multiple ways, both positively and negatively. One of the new attractive directions in microbiome biology is the “microbiome-brain axis”. Several groups of researchers have described the ability of the gut microbiota to communicate with the brain and thus modulate human behavior. These limited experimental data became the foundation of the “biomeme hypothesis” of possible microbial origin of some religious rituals that has recently appeared in Biology Direct. Here I propose a critical analysis of this hypothesis. I conclude that there is no evidence of the microbial origin of religious practices but there are strong indications of their psychological and social roots.
Reviewers
This article was reviewed by Eugene Koonin, Neil R Smalheiser, Etienne Joly.
doi:10.1186/s13062-014-0025-6
PMCID: PMC4265476  PMID: 25433677
Microbes; Religious rituals; Microbiome-brain axis; Biomeme hypothesis; Popper; Falsifiability; Occam’s razor
14.  Cooperation and selfishness both occur during molecular evolution 
Biology Direct  2014;10:26.
Perhaps the ‘selfish’ aspect of evolution has been over-emphasised, and organisms considered as basically selfish. However, at the macromolecular level of genes and proteins the cooperative aspect of evolution is more obvious and balances this self-centred aspect. Thousands of proteins must function together in an integrated manner to use and to produce the many molecules necessary for a functioning cell. The macromolecules have no idea whether they are functioning cooperatively or competitively with other genes and gene products (such as proteins). The cell is a giant cooperative system of thousands of genes/proteins that function together, even if it has to simultaneously resist ‘parasites’. There are extensive examples of cooperative behavior among genes and proteins in both functioning cells and in the origin of life, so this cooperative nature, along with selfishness, must be considered part of normal evolution. The principles also apply to very large numbers of examples of ‘positive interactions’ between organisms, including both eukaryotes and akaryotes (prokaryotes). This does not negate in any way the ‘selfishness’ of genes – but macromolecules have no idea when they are helping, or hindering, other groups of macromolecules. We need to assert more strongly that genes, and gene products, function together as a cooperative unit.
Reviewers: This article was reviewed by Prof. Bill Martin (Düsseldorf), Dr. Nicolas Galtier (Montpellier) and Dr. Anthony Poole (Christchurch).
doi:10.1186/s13062-014-0026-5
PMCID: PMC4266915  PMID: 25486885
Cooperation; Molecular evolution; Molecular level; Origin of life; Natural selection
15.  Chordopoxvirus protein F12 implicated in enveloped virion morphogenesis is an inactivated DNA polymerase 
Biology Direct  2014;9:22.
Through the course of their evolution, viruses with large genomes have acquired numerous host genes, most of which perform function in virus reproduction in a manner that is related to their original activities in the cells, but some are exapted for new roles. Here we report the unexpected finding that protein F12, which is conserved among the chordopoxviruses and is implicated in the morphogenesis of enveloped intracellular virions, is a derived DNA polymerase, possibly of bacteriophage origin, in which the polymerase domain and probably the exonuclease domain have been inactivated. Thus, F12 appears to present a rare example of a drastic, exaptive functional change in virus evolution.
Reviewers: This article was reviewed by Frank Eisenhaber and Juergen Brosius. For complete reviews, go the Reviewers’ Reports section.
doi:10.1186/1745-6150-9-22
PMCID: PMC4304020  PMID: 25374149
DNA polymerase; Exaptation; Poxviruses; Evolution of viruses
16.  Putative roles of purinergic signaling in human immunodeficiency virus-1 infection 
Biology Direct  2014;9:21.
Reviewers
This article was reviewed by Neil S. Greenspan and Rachel Gerstein.
Nucleotides and nucleosides act as potent extracellular messengers via the activation of the family of cell-surface receptors termed purinergic receptors. These receptors are categorized into P1 and P2 receptors (P2Rs). P2Rs are further classified into two distinct families, P2X receptors (P2XRs) and P2Y receptors (P2YRs). These receptors display broad tissue distribution throughout the body and are involved in several biological events. Immune cells express various P2Rs, and purinergic signaling mechanisms have been shown to play key roles in the regulation of many aspects of immune responses. Researchers have elucidated the involvement of these receptors in the host response to infections. The evidences indicate a dual function of these receptors, depending on the microorganism and the cellular model involved. Three recent reports have examined the relationship between the level of extracellular ATP, the mechanisms underlying purinergic receptors participating in the infection mechanism of HIV-1 in the cell. Although preliminary, these results indicate that purinergic receptors are putative pharmacological targets that should be further explored in future studies.
doi:10.1186/1745-6150-9-21
PMCID: PMC4218944  PMID: 25351961
P2X7R; HIV-1 infection; Antagonists; Pharmacological targets
17.  A new rhesus macaque assembly and annotation for next-generation sequencing analyses 
Biology Direct  2014;9:20.
Background
The rhesus macaque (Macaca mulatta) is a key species for advancing biomedical research. Like all draft mammalian genomes, the draft rhesus assembly (rheMac2) has gaps, sequencing errors and misassemblies that have prevented automated annotation pipelines from functioning correctly. Another rhesus macaque assembly, CR_1.0, is also available but is substantially more fragmented than rheMac2 with smaller contigs and scaffolds. Annotations for these two assemblies are limited in completeness and accuracy. High quality assembly and annotation files are required for a wide range of studies including expression, genetic and evolutionary analyses.
Results
We report a new de novo assembly of the rhesus macaque genome (MacaM) that incorporates both the original Sanger sequences used to assemble rheMac2 and new Illumina sequences from the same animal. MacaM has a weighted average (N50) contig size of 64 kilobases, more than twice the size of the rheMac2 assembly and almost five times the size of the CR_1.0 assembly. The MacaM chromosome assembly incorporates information from previously unutilized mapping data and preliminary annotation of scaffolds. Independent assessment of the assemblies using Ion Torrent read alignments indicates that MacaM is more complete and accurate than rheMac2 and CR_1.0. We assembled messenger RNA sequences from several rhesus tissues into transcripts which allowed us to identify a total of 11,712 complete proteins representing 9,524 distinct genes. Using a combination of our assembled rhesus macaque transcripts and human transcripts, we annotated 18,757 transcripts and 16,050 genes with complete coding sequences in the MacaM assembly. Further, we demonstrate that the new annotations provide greatly improved accuracy as compared to the current annotations of rheMac2. Finally, we show that the MacaM genome provides an accurate resource for alignment of reads produced by RNA sequence expression studies.
Conclusions
The MacaM assembly and annotation files provide a substantially more complete and accurate representation of the rhesus macaque genome than rheMac2 or CR_1.0 and will serve as an important resource for investigators conducting next-generation sequencing studies with nonhuman primates.
Reviewers
This article was reviewed by Dr. Lutz Walter, Dr. Soojin Yi and Dr. Kateryna Makova.
doi:10.1186/1745-6150-9-20
PMCID: PMC4214606  PMID: 25319552
Macaca mulatta; Rhesus macaque; Genome; Assembly; Annotation; Transcriptome; Next-generation sequencing
18.  Mycobacteriophage-drived diversification of Mycobacterium abscessus 
Biology Direct  2014;9:19.
Background
Mycobacterium abscessus is an emerging opportunistic pathogen which diversity was acknowledged by the recent description of two subspecies accommodating M. abscessus, Mycobacterium bolletii and Mycobacterium massiliense isolates.
Results
Here, genome analysis found 1–8 prophage regions in 47/48 M. abscessus genomes ranging from small prophage-like elements to complete prophages. A total of 20,304 viral and phage proteins clustered into 853 orthologous groups. Phylogenomic and phylogenetic analyses based on prophage region homology found three main clusters corresponding to M. abscessus, M. bolletii and M. massiliense. Analysing 135 annotated Tape Measure Proteins found thirteen clusters and four singletons, suggesting that at least 17 mycobacteriophages had infected M. abscessus during its evolution. The evolutionary history of phages differed from that of their mycobacterial hosts. In particular, 33 phage-related proteins have been horizontally transferred within M. abscessus genomes. They comprise of an integrase, specific mycobacteriophage proteins, hypothetical proteins and DNA replication and metabolism proteins. Gene exchanges, loss and gains which occurred in M. abscessus genomes have been driven by several mycobacteriophages.
Conclusions
This analysis of phage-mycobacterium co-evolution suggests that mycobacteriophages are playing a key-role in the on-going diversification of M. abscessus.
Reviewers
This article was reviewed by Eric Bapteste, Patrick Forterre and Eugene Koonin.
doi:10.1186/1745-6150-9-19
PMCID: PMC4172396  PMID: 25224692
Mycobacterium abscessus; Mycobacterium bolletii; Mycobacterium massiliense; Prophages; Mycobacteriophages
19.  Parallel universes of Black Six biology 
Biology Direct  2014;9:18.
Creation of lethal and synthetic lethal mutations in an experimental organism is a cornerstone of genetic dissection of gene function, and is related to the concept of an essential gene. Common inbred mouse strains carry background mutations, which can act as genetic modifiers, interfering with the assignment of gene essentiality. The inbred strain C57BL/6J, commonly known as “Black Six”, stands out, as it carries a spontaneous homozygous deletion in the nicotinamide nucleotide transhydrogenase (Nnt) gene [GenBank: AH009385.2], resulting in impairment of steroidogenic mitochondria of the adrenal gland, and a multitude of indirect modifier effects, coming from alteration of glucocorticoid-regulated processes. Over time, the popular strain has been used, by means of gene targeting technology, to assign “essential” and “redundant” qualifiers to numerous genes, thus creating an internally consistent “parallel universe” of knowledge. It is unrealistic to suggest phasing-out of this strain, given the scope of shared resources built around it, however, continuing on the road of “strain-unawareness” will result in profound waste of effort, particularly where translational research is concerned. The review analyzes the historical roots of this phenomenon and proposes that building of “parallel universes” should be urgently made visible to a critical reader by obligatory use of unambiguous and persistent tags in publications and databases, such as hypertext links, pointing to a vendor’s strain description web page, or to a digital object identifier (d.o.i.) of the original publication, so that any research done exclusively in C57BL/6J, could be easily identified.
Reviewers
This article was reviewed by Dr. Neil Smalheiser and Dr. Miguel Andrade-Navarro.
doi:10.1186/1745-6150-9-18
PMCID: PMC4108611  PMID: 25038798
Mouse; Inbred strain; C57BL/6J; Synthetic lethality; Gene interaction; Essential gene; Nicotinamide nucleotide transhydrogenase; Mitochondria; Glucocorticoid hormone; Adrenal gland
20.  Translational selection in human: more pronounced in housekeeping genes 
Biology Direct  2014;9:17.
Background
Translational selection is a ubiquitous and significant mechanism to regulate protein expression in prokaryotes and unicellular eukaryotes. Recent evidence has shown that translational selection is weakly operative in highly expressed genes in human and other vertebrates. However, it remains unclear whether translational selection acts differentially on human genes depending on their expression patterns.
Results
Here we report that human housekeeping (HK) genes that are strictly defined as genes that are expressed ubiquitously and consistently in most or all tissues, are under stronger translational selection.
Conclusions
These observations clearly show that translational selection is also closely associated with expression pattern. Our results suggest that human HK genes are more efficiently and/or accurately translated into proteins, which will inevitably open up a new understanding of HK genes and the regulation of gene expression.
Reviewers
This article was reviewed by Yuan Yuan, Baylor College of Medicine; Han Liang, University of Texas MD Anderson Cancer Center (nominated by Dr Laura Landweber) Eugene Koonin, NCBI, NLM, NIH, United States of America Sandor Pongor, International Centre for Genetic Engineering and biotechnology (ICGEB), Italy.
doi:10.1186/1745-6150-9-17
PMCID: PMC4100034  PMID: 25011537
Translational selection; Codon usage bias; Expression regulation; Housekeeping gene; Tissue-specific gene
21.  Impairment of translation in neurons as a putative causative factor for autism 
Biology Direct  2014;9:16.
Background
A dramatic increase in the prevalence of autism and Autistic Spectrum Disorders (ASD) has been observed over the last two decades in USA, Europe and Asia. Given the accumulating data on the possible role of translation in the etiology of ASD, we analyzed potential effects of rare synonymous substitutions associated with ASD on mRNA stability, splicing enhancers and silencers, and codon usage.
Presentation of the hypothesis
We hypothesize that subtle impairment of translation, resulting in dosage imbalance of neuron-specific proteins, contributes to the etiology of ASD synergistically with environmental neurotoxins.
Testing the hypothesis
A statistically significant shift from optimal to suboptimal codons caused by rare synonymous substitutions associated with ASD was detected whereas no effect on other analyzed characteristics of transcripts was identified. This result suggests that the impact of rare codons on the translation of genes involved in neuron development, even if slight in magnitude, could contribute to the pathogenesis of ASD in the presence of an aggressive chemical background. This hypothesis could be tested by further analysis of ASD-associated mutations, direct biochemical characterization of their effects, and assessment of in vivo effects on animal models.
Implications of the hypothesis
It seems likely that the synergistic action of environmental hazards with genetic variations that in themselves have limited or no deleterious effects but are potentiated by the environmental factors is a general principle that underlies the alarming increase in the ASD prevalence.
Reviewers
This article was reviewed by Andrey Rzhetsky, Neil R. Smalheiser, and Shamil R. Sunyaev.
doi:10.1186/1745-6150-9-16
PMCID: PMC4099083  PMID: 25011470
Synonymous mutations; Single nucleotide polymorphism; Codon usage; Splicing enhancer; Splicing silencer; mRNA secondary structure; Transcription factor binding; Neurotoxin
22.  Exploring the stability of long intergenic non-coding RNA in K562 cells by comparative studies of RNA-Seq datasets 
Biology Direct  2014;9:15.
Background
The stability of long intergenic non-coding RNAs (lincRNAs) that possess tissue/cell-specific expression, might be closely related to their physiological functions. However, the mechanism associated with stability of lincRNA remains elusive. In this study, we try to study the stability of lincRNA in K562 cells, an important model cell, through comparing two K562 transcriptomes which are obtained from ENCODE Consortium and our sequenced RNA-Seq dataset (PH) respectively.
Results
By lincRNAs analysis pipeline, 1804 high-confidence lincRNAs involving 1564 annotated lincRNAs and 240 putative novel lincRNAs were identified in PH, and 1587 high-confidence lincRNAs including 1429 annotated lincRNAs and 158 putative novel lincRNAs in ENCODE. There are 1009 unique lincRNAs in PH, 792 unique lincRNAs were in ENCODE, and 795 overlapping lincRNAs in both datasets. The analysis of differences in minimum free energy distribution and lincRNA half-life showed that a large proportion of overlapping lincRNAs were more stable than the unique lincRNAs. Most lincRNAs were more unstable than protein-coding RNAs through comparing their minimum free energy.
Conclusions
Identification of overlapping and unique lincRNAs can be helpful to classify the stability of lincRNAs. Our results suggest that overlapping lincRNAs (relatively stable linRNAs) and unique lincRNAs (relatively unstable lincRNAs) might be involved in different cellular processes.
Reviewers
This article has been reviewed by Prof. Oliviero Carugo, Dr. Alistair Forrest and Prof. Manju Bansal.
doi:10.1186/1745-6150-9-15
PMCID: PMC4094694  PMID: 24996425
RNA Sequencing (RNA-Seq); Long intergenic non-coding RNAs (lincRNAs); K562; RNA stability
23.  Midichlorians - the biomeme hypothesis: is there a microbial component to religious rituals? 
Biology Direct  2014;9:14.
Background
Cutting edge research of human microbiome diversity has led to the development of the microbiome-gut-brain axis concept, based on the idea that gut microbes may have an impact on the behavior of their human hosts. Many examples of behavior-altering parasites are known to affect members of the animal kingdom. Some prominent examples include Ophiocordyceps unilateralis (fungi), Toxoplasma gondii (protista), Wolbachia (bacteria), Glyptapanteles sp. (arthropoda), Spinochordodes tellinii (nematomorpha) and Dicrocoelium dendriticum (flat worm). These organisms belong to a very diverse set of taxonomic groups suggesting that the phenomena of parasitic host control might be more common in nature than currently established and possibly overlooked in humans.
Presentation of the hypothesis
Some microorganisms would gain an evolutionary advantage by encouraging human hosts to perform certain rituals that favor microbial transmission. We hypothesize that certain aspects of religious behavior observed in the human society could be influenced by microbial host control and that the transmission of some religious rituals could be regarded as the simultaneous transmission of both ideas (memes) and parasitic organisms.
Testing the hypothesis
We predict that next-generation microbiome sequencing of samples obtained from gut or brain tissues of control subjects and subjects with a history of voluntary active participation in certain religious rituals that promote microbial transmission will lead to the discovery of microbes, whose presence has a consistent and positive association with religious behavior. Our hypothesis also predicts a decline of participation in religious rituals in societies with improved sanitation.
Implications of the hypothesis
If proven true, our hypothesis may provide insights on the origin and pervasiveness of certain religious practices and provide an alternative explanation for recently published positive associations between parasite-stress and religiosity. The discovery of novel microorganisms that affect host behavior may improve our understanding of neurobiology and neurochemistry, while the diversity of such organisms may be of interest to evolutionary biologists and religious scholars.
Reviewers
This article was reviewed by Prof. Dan Graur, Dr. Rob Knight and Dr. Eugene Koonin
doi:10.1186/1745-6150-9-14
PMCID: PMC4094439  PMID: 24990702
Microbiome; Religion; Brain; Metagenome; Midichlorians; Biomeme; Behavior; Rituals
24.  Pseudo-chaotic oscillations in CRISPR-virus coevolution predicted by bifurcation analysis 
Biology Direct  2014;9:13.
Background
The CRISPR-Cas systems of adaptive antivirus immunity are present in most archaea and many bacteria, and provide resistance to specific viruses or plasmids by inserting fragments of foreign DNA into the host genome and then utilizing transcripts of these spacers to inactivate the cognate foreign genome. The recent development of powerful genome engineering tools on the basis of CRISPR-Cas has sharply increased the interest in the diversity and evolution of these systems. Comparative genomic data indicate that during evolution of prokaryotes CRISPR-Cas loci are lost and acquired via horizontal gene transfer at high rates. Mathematical modeling and initial experimental studies of CRISPR-carrying microbes and viruses reveal complex coevolutionary dynamics.
Results
We performed a bifurcation analysis of models of coevolution of viruses and microbial host that possess CRISPR-Cas hereditary adaptive immunity systems. The analyzed Malthusian and logistic models display complex, and in particular, quasi-chaotic oscillation regimes that have not been previously observed experimentally or in agent-based models of the CRISPR-mediated immunity. The key factors for the appearance of the quasi-chaotic oscillations are the non-linear dependence of the host immunity on the virus load and the partitioning of the hosts into the immune and susceptible populations, so that the system consists of three components.
Conclusions
Bifurcation analysis of CRISPR-host coevolution model predicts complex regimes including quasi-chaotic oscillations. The quasi-chaotic regimes of virus-host coevolution are likely to be biologically relevant given the evolutionary instability of the CRISPR-Cas loci revealed by comparative genomics. The results of this analysis might have implications beyond the CRISPR-Cas systems, i.e. could describe the behavior of any adaptive immunity system with a heritable component, be it genetic or epigenetic. These predictions are experimentally testable.
Reviewers’ reports
This manuscript was reviewed by Sandor Pongor, Sergei Maslov and Marek Kimmel. For the complete reports, go to the Reviewers’ Reports section.
doi:10.1186/1745-6150-9-13
PMCID: PMC4096434  PMID: 24986220
25.  Selecting biologically informative genes in co-expression networks with a centrality score 
Biology Direct  2014;9:12.
Background
Measures of node centrality in biological networks are useful to detect genes with critical functional roles. In gene co-expression networks, highly connected genes (i.e., candidate hubs) have been associated with key disease-related pathways. Although different approaches to estimating gene centrality are available, their potential biological relevance in gene co-expression networks deserves further investigation. Moreover, standard measures of gene centrality focus on binary interaction networks, which may not always be suitable in the context of co-expression networks. Here, I also investigate a method that identifies potential biologically meaningful genes based on a weighted connectivity score and indicators of statistical relevance.
Results
The method enables a characterization of the strength and diversity of co-expression associations in the network. It outperformed standard centrality measures by highlighting more biologically informative genes in different gene co-expression networks and biological research domains. As part of the illustration of the gene selection potential of this approach, I present an application case in zebrafish heart regeneration. The proposed technique predicted genes that are significantly implicated in cellular processes required for tissue regeneration after injury.
Conclusions
A method for selecting biologically informative genes from gene co-expression networks is provided, together with free open software.
Reviewers
This article was reviewed by Anthony Almudevar, Maciej M Kańduła (nominated by David P Kreil) and Christine Wells.
doi:10.1186/1745-6150-9-12
PMCID: PMC4079186  PMID: 24947308
Network hubs; Weighted networks; Gene co-expression networks; Centrality scores; Zebrafish; Heart regeneration; Cancer; Microarrays; RNA-Seq

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