233 research outputs found

    Epigenetic changes mediated by polycomb repressive complex 2 and E2a are associated with drug resistance in a mouse model of lymphoma

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    Background: The genetic origins of chemotherapy resistance are well established; however the role of epigenetics in drug resistance is less well understood To investigate mechanisms of drug resistance we performed systematic genetic epigenetic and transcriptomic analyses of an alkylating agent-sensitive murine lymphoma cell line and a series of resistant lines derived by drug dose escalation   Methods: Dose escalation of the alkylating agent mafosfamide was used to create a series of increasingly drugresistant mouse Burkitt's lymphoma cell lines Whole genome sequencing DNA microarrays reduced representation bisulfite sequencing and chromatin immunoprecipitation sequencing were used to identify alterations in DNA sequence mRNA expression CpG methylation and H3K27me3 occupancy respectively that were associated with increased resistance   Results: Our data suggest that acquired resistance cannot be explained by genetic alterations Based on integration of transcriptional profiles with transcription factor binding data we hypothesize that resistance is driven by epigenetic plasticity We observed that the resistant cells had H3K27me3 and DNA methylation profiles distinct from those of the parental lines Moreover we observed DNA methylation changes in the promoters of genes regulated by E2a and members of the polycomb repressor complex 2 (PRC2) and differentially expressed genes were enriched for targets of E2a The integrative analysis considering H3K27me3 further supported a role for PRC2 in mediating resistance By integrating our results with data from the Immunological Genome Project (Immgenorg) we showed that these transcriptional changes track the B-cell maturation axis   Conclusions: Our data suggest a novel mechanism of drug resistance in which E2a and PRC2 drive changes in the B-cell epigenome; these alterations attenuate alkylating agent treatment-induced apoptosi

    Phylogeny of Prokaryotes and Chloroplasts Revealed by a Simple Composition Approach on All Protein Sequences from Complete Genomes Without Sequence Alignment

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    The complete genomes of living organisms have provided much information on their phylogenetic relationships. Similarly, the complete genomes of chloroplasts have helped to resolve the evolution of this organelle in photosynthetic eukaryotes. In this paper we propose an alternative method of phylogenetic analysis using compositional statistics for all protein sequences from complete genomes. This new method is conceptually simpler than and computationally as fast as the one proposed by Qi et al. (2004b) and Chu et al. (2004). The same data sets used in Qi et al. (2004b) and Chu et al. (2004) are analyzed using the new method. Our distance-based phylogenic tree of the 109 prokaryotes and eukaryotes agrees with the biologists tree of life based on 16S rRNA comparison in a predominant majority of basic branching and most lower taxa. Our phylogenetic analysis also shows that the chloroplast genomes are separated to two major clades corresponding to chlorophytes s.l. and rhodophytes s.l. The interrelationships among the chloroplasts are largely in agreement with the current understanding on chloroplast evolution

    Informed design of educational technology for teaching and learning? Towards an evidence-informed model of good practice

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    The aim of this paper is to model evidence-informed design based on a selective critical analysis of research articles. We draw upon findings from an investigation into practitioners’ use of educational technologies to synthesise and model what informs their designs. We found that practitioners’ designs were often driven by implicit assumptions about learning. These shaped both the design of interventions and the methods sought to derive evaluations and interpret the findings. We argue that interventions need to be grounded in better and explicit conceptualisations of what constitutes learning in order to have well-informed designs that focus on improving the quality of student learning

    Systematic Reviews in Educational Research: Methodology, Perspectives and Application

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    This chapter explores the processes of reviewing literature as a research method. The logic of the family of research approaches called systematic review is analysed and the variation in techniques used in the different approaches explored using examples from existing reviews. The key distinctions between aggregative and configurative approaches are illustrated and the chapter signposts further reading on key issues in the systematic review process

    The Genomics of Disulfide Bonding and Protein Stabilization in Thermophiles

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    Thermophilic organisms flourish in varied high-temperature environmental niches that are deadly to other organisms. Recently, genomic evidence has implicated a critical role for disulfide bonds in the structural stabilization of intracellular proteins from certain of these organisms, contrary to the conventional view that structural disulfide bonds are exclusively extracellular. Here both computational and structural data are presented to explore the occurrence of disulfide bonds as a protein-stabilization method across many thermophilic prokaryotes. Based on computational studies, disulfide-bond richness is found to be widespread, with thermophiles containing the highest levels. Interestingly, only a distinct subset of thermophiles exhibit this property. A computational search for proteins matching this target phylogenetic profile singles out a specific protein, known as protein disulfide oxidoreductase, as a potential key player in thermophilic intracellular disulfide-bond formation. Finally, biochemical support in the form of a new crystal structure of a thermophilic protein with three disulfide bonds is presented together with a survey of known structures from the literature. Together, the results provide insight into biochemical specialization and the diversity of methods employed by organisms to stabilize their proteins in exotic environments. The findings also motivate continued efforts to sequence genomes from divergent organisms
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