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  • 1
    Language: English
    In: Bacteriophage, 01 January 2015, p.00-00
    Description: A key event in the lifecycle of a temperate bacteriophage is the choice between lysis and lysogeny upon infection of a susceptible host cell. In a recent paper, we showed that a prolonged period exists after the decision to lysogenize, during which bacteriophage λ can abandon the initial decision, and instead develop lytically, as a response to the accumulation of the late lytic regulatory protein Q. Here, we present evidence that expression of Q does not induce replication of λ DNA, suggesting that the DNA to be packaged into the resulting phage progeny was already present at the time of the initial decision to lysogenize. We summarize our findings in a working model of the key determinants of the duration of the post-decision period during which it is possible for the infected cell to switch from the lysogeny decision to successful lytic development. Article just-accepted.
    Keywords: Bacteriophage Λ ; Lysis-Lysogeny Decision ; Cell Fate Commitment ; Dna Replication ; Gene Regulatory Circuit
    ISSN: 21597073
    E-ISSN: 2159-7081
    E-ISSN: 19326203
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  • 2
    In: Nature, 2016, Vol.534(7605), p.41
    Keywords: Microbiology ; Antibiotics ; Microbial Drug Resistance;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 3
    Language: English
    In: Nature, June 2, 2016, Vol.534(7605), p.41(2)
    Description: In bacterial persistence, a small fraction of an antibiotic-sensitive cell population has switched to a slow-growing or dormant state, and is drug tolerant1,2. This differs from antibiotic resistance in that regrowth of a persistent population results in the same percentage of drug-sensitive cells as before. Persistence has been interpreted as a bet-hedging strategy that increases the survival rates of bacterial populations3,4, and is medically relevant because it might sustain recurrent and chronic infections. Writing in Molecular Cell, Pu et al.5 challenge the widespread view that persistence is a passive state. The authors demonstrate that persister cells use an energy-dependent efflux pump protein called TolC to actively reduce the intracellular accumulation of antibiotic - a finding that might have both fundamental and therapeutic relevance.
    Keywords: Microbial Drug Resistance – Research
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 4
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 20 July 2010, Vol.107(29), pp.12998-3003
    Description: Gene regulatory networks are based on simple building blocks such as promoters, transcription factors (TFs) and their binding sites on DNA. But how diverse are the functions that can be obtained by different arrangements of promoters and TF binding sites? In this work we constructed synthetic regulatory regions using promoter elements and binding sites of two noninteracting TFs, each sensing a single environmental input signal. We show that simply by combining these three kinds of elements, we can obtain 11 of the 16 Boolean logic gates that integrate two environmental signals in vivo. Further, we demonstrate how combination of logic gates can result in new logic functions. Our results suggest that simple elements of transcription regulation form a highly flexible toolbox that can generate diverse functions under natural selection.
    Keywords: Escherichia Coli -- Genetics ; Gene Regulatory Networks -- Genetics
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 5
    Language: English
    In: Journal of bacteriology, October 2014, Vol.196(20), pp.3582-8
    Description: A key event in development is the irreversible commitment to a particular cell fate, which may be concurrent with or delayed with respect to the initial cell fate decision. In this work, we use the paradigmatic bacteriophage λ lysis-lysogeny decision circuit to study the timing of commitment. The lysis-lysogeny decision is made based on the expression trajectory of CII. The chosen developmental strategy is manifested by repression of the pR and pL promoters by CI (lysogeny) or by antitermination of late gene expression by Q (lysis). We found that expression of Q in trans from a plasmid at the time of infection resulted in a uniform lytic decision. Furthermore, expression of Q up to 50 min after infection results in lysis of the majority of cells which initially chose lysogenic development. In contrast, expression of Q in cells containing a single chromosomal prophage had no effect on cell growth, indicating commitment to lysogeny. Notably, if the prophage was present in 10 plasmid-borne copies, Q expression resulted in lytic development, suggesting that the cellular phage chromosome number is the critical determinant of the timing of lysogenic commitment. Based on our results, we conclude that (i) the lysogenic decision made by the CI-Cro switch soon after infection can be overruled by ectopic Q expression at least for a time equivalent to one phage life cycle, (ii) the presence of multiple λ chromosomes is a prerequisite for a successful Q-mediated switch from lysogenic to lytic development, and (iii) phage chromosomes within the same cell can reach different decisions.
    Keywords: Bacteriophage Lambda ; Lysogeny ; Escherichia Coli -- Virology ; Gene Expression Regulation, Viral -- Physiology ; Viral Proteins -- Metabolism
    ISSN: 00219193
    E-ISSN: 1098-5530
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  • 6
    Language: English
    In: PLoS ONE, 2011, Vol.6(9), p.e25394
    Description: ‘Fine-tuning’ of protein abundance makes microRNAs (miRNAs) pervasively implicated in human biology. Although targeting many mRNAs endows the power of single miRNA to regulate complex biological processes, its functional roles in a particular tissue will be inevitably restricted because only a subset of its target genes is expressed. ; Here, we analyze the characteristics of miRNA regulation upon target genes according to tissue-specific gene expression by constructing tissue-specific protein interaction networks for ten main types of tissues in the human body. ; Commonly expressed proteins are under more intensive but lower-cost miRNAs control than proteins with the tissue-specific expression. MiRNAs that target more commonly expressed genes usually regulate more tissue-specific genes. This is consistent with the previous finding that tissue-specific proteins tend to be functionally connected with commonly expressed proteins. But to a particular miRNA such a balance is not invariable among different tissues implying diverse tissue regulation modes executed by miRNAs. ; These results suggest miRNAs that interact with more commonly expressed genes can be expected to play important tissue-specific roles.
    Keywords: Research Article ; Biology ; Genetics And Genomics ; Computational Biology
    E-ISSN: 1932-6203
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  • 7
    Language: English
    In: 2012, Vol.7(8), p.e44175
    Description: So far, investigators have found numerous tumor suppressor genes (TSGs) and oncogenes (OCGs) that control cell proliferation and apoptosis during cancer development. Furthermore, TSGs and OCGs may act as modulators of transcription factors (TFs) to influence gene regulation. A comprehensive investigation of TSGs, OCGs, TFs, and their joint target genes at the network level may provide a deeper understanding of the post-translational modulation of TSGs and OCGs to TF gene regulation. ; In this study, we developed a novel computational framework for identifying target genes of TSGs and OCGs using TFs as bridges through the integration of protein-protein interactions and gene expression data. We applied this pipeline to ovarian cancer and constructed a three-layer regulatory network. In the network, the top layer was comprised of modulators (TSGs and OCGs), the middle layer included TFs, and the bottom layer contained target genes. Based on regulatory relationships in the network, we compiled TSG and OCG profiles and performed clustering analyses. Interestingly, we found TSGs and OCGs formed two distinct branches. The genes in the TSG branch were significantly enriched in DNA damage and repair, regulating macromolecule metabolism, cell cycle and apoptosis, while the genes in the OCG branch were significantly enriched in the ErbB signaling pathway. Remarkably, their specific targets showed a reversed functional enrichment in terms of apoptosis and the ErbB signaling pathway: the target genes regulated by OCGs only were enriched in anti-apoptosis and the target genes regulated by TSGs only were enriched in the ErbB signaling pathway. ; This study provides the first comprehensive investigation of the interplay of TSGs and OCGs in a regulatory network modulated by TFs. Our application in ovarian cancer revealed distinct regulatory patterns of TSGs and OCGs, suggesting a competitive regulatory mechanism acting upon apoptosis and the ErbB signaling pathway through their specific target genes.
    Keywords: Research Article ; Biology ; Medicine ; Genetics And Genomics ; Computational Biology ; Cell Biology ; Oncology
    E-ISSN: 1932-6203
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  • 8
    Language: English
    In: PLoS ONE, 2012, Vol.7(1), p.e30232
    Description: Boolean-based method, despite of its simplicity, would be a more attractive approach for inferring a network from high-throughput expression data if its effectiveness has not been limited by high false positive prediction. In this study, we explored factors that could simply be adjusted to improve the accuracy of inferring networks. Our work focused on the analysis of the effects of discretisation methods, biological constraints, and stringency of Boolean function assignment on the performance of Boolean network, including accuracy , precision , specificity and sensitivity , using three sets of microarray time-series data. The study showed that biological constraints have pivotal influence on the network performance over the other factors. It can reduce the variation in network performance resulting from the arbitrary selection of discretisation methods and stringency settings. We also presented the master Boolean network as an approach to establish the unique solution for Boolean analysis. The information acquired from the analysis was summarised and deployed as a general guideline for an efficient use of Boolean-based method in the network inference. In the end, we provided an example of the use of such a guideline in the study of Arabidopsis circadian clock genetic network from which much interesting biological information can be inferred.
    Keywords: Research Article ; Biology ; Mathematics ; Genetics And Genomics ; Plant Biology ; Computational Biology ; Mathematics
    E-ISSN: 1932-6203
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  • 9
    Language: English
    In: PLoS ONE, 2011, Vol.6(10), p.e25642
    Description: The design of small interfering RNA (siRNA) is a multi factorial problem that has gained the attention of many researchers in the area of therapeutic and functional genomics. MysiRNA score was previously introduced that improves the correlation of siRNA activity prediction considering state of the art algorithms. In this paper, a new program, MysiRNA-Designer , is described which integrates several factors in an automated work-flow considering mRNA transcripts variations, siRNA and mRNA target accessibility, and both near-perfect and partial off-target matches. It also features the MysiRNA score, a highly ranked correlated siRNA efficacy prediction score for ranking the designed siRNAs, in addition to top scoring models Biopredsi, DISR, Thermocomposition21 and i-Score, and integrates them in a unique siRNA score-filtration technique. This multi-score filtration layer filters siRNA that passes the 90% thresholds calculated from experimental dataset features. MysiRNA-Designer takes an accession, finds conserved regions among its transcript space, finds accessible regions within the mRNA, designs all possible siRNAs for these regions, filters them based on multi-scores thresholds, and then performs SNP and off-target filtration. These strict selection criteria were tested against human genes in which at least one active siRNA was designed from 95.7% of total genes. In addition, when tested against an experimental dataset, MysiRNA-Designer was found capable of rejecting 98% of the false positive siRNAs, showing superiority over three state of the art siRNA design programs. MysiRNA is a freely accessible (Microsoft Windows based) desktop application that can be used to design siRNA with a high accuracy and specificity. We believe that MysiRNA-Designer has the potential to play an important role in this area.
    Keywords: Research Article ; Biology ; Computer Science ; Genetics And Genomics ; Biotechnology ; Computational Biology ; Computer Science
    E-ISSN: 1932-6203
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  • 10
    Language: English
    In: PLoS ONE, 2012, Vol.7(5), p.e36498
    Description: Several earlier studies have described an unusual exclusion phenotype exhibited by cells with plasmids carrying a portion of the replication region of phage lambda. Cells exhibiting this inhibition phenotype (IP) prevent the plating of homo-immune and hybrid hetero-immune lambdoid phages. We have attempted to define aspects of IP, and show that it is directed to rep λ phages. IP was observed in cells with plasmids containing a λ DNA fragment including oop , encoding a short OOP micro RNA, and part of the lambda origin of replication, ori λ, defined by iteron sequences ITN1-4 and an adjacent high AT-rich sequence. Transcription of the intact oop sequence from its promoter, p O is required for IP, as are iterons ITN3–4, but not the high AT-rich portion of ori λ. The results suggest that IP silencing is directed to theta mode replication initiation from an infecting rep λ genome, or an induced rep λ prophage. Phage mutations suppressing IP, i.e., Sip, map within, or adjacent to cro or in O , or both. Our results for plasmid based IP suggest the hypothesis that there is a natural mechanism for silencing early theta-mode replication initiation, i.e. the buildup of λ genomes with oop + ori λ + sequence.
    Keywords: Research Article ; Biology ; Genetics And Genomics ; Virology ; Microbiology
    E-ISSN: 1932-6203
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