3,006 research outputs found
Colin Humphris
No full text"Colin Humphris 2 Sqdrn. RAAF. 1941 - 1942 Author of - 'Trapped on Timor' (as a result of bombing of Darwin Feb. 19, 1942)".Colin Humphris. 2 Squadron, Royal Australian Air Force 1941 - 1942. Author of - 'Trapped on Timor' (as a result of bombing of Darwin February 19, 1942)
Integrative modeling reveals the principles of multi-scale chromatin boundary formation in human nuclear organization
Full text linkBACKGROUND: Interphase chromosomes adopt a hierarchical structure, and recent data have characterized their chromatin organization at very different scales, from sub-genic regions associated with DNA-binding proteins at the order of tens or hundreds of bases, through larger regions with active or repressed chromatin states, up to multi-megabase-scale domains associated with nuclear positioning, replication timing and other qualities. However, we have lacked detailed, quantitative models to understand the interactions between these different strata.RESULTS: Here we collate large collections of matched locus-level chromatin features and Hi-C interaction data, representing higher-order organization, across three human cell types. We use quantitative modeling approaches to assess whether locus-level features are sufficient to explain higher-order structure, and identify the most influential underlying features. We identify structurally variable domains between cell types and examine the underlying features to discover a general association with cell-type-specific enhancer activity. We also identify the most prominent features marking the boundaries of two types of higher-order domains at different scales: topologically associating domains and nuclear compartments. We find parallel enrichments of particular chromatin features for both types, including features associated with active promoters and the architectural proteins CTCF and YY1.CONCLUSIONS: We show that integrative modeling of large chromatin dataset collections using random forests can generate useful insights into chromosome structure. The models produced recapitulate known biological features of the cell types involved, allow exploration of the antecedents of higher-order structures and generate testable hypotheses for further experimental studies.</p
Conservation and divergence in higher order chromatin structure
Full text linkAspects of higher order chromatin structure such as replication timing, lamina association and Hi-C inter-locus interactions have been recently studied in
several human and mouse cell types and it has been suggested that most of these
features of genome organisation are conserved over evolution. However, the extent
of evolutionary divergence in higher order structure has not been rigorously
measured across the mammalian genome, and little is known about the characteristics of any divergent loci defined. Here we generate an orthologous
dataset combining multiple measurements of chromatin structure and organisation
over many embryonic cell types for both human and mouse that, for the first time,
allows a comprehensive assessment of the extent of structural divergence between
different mammalian genomes. Comparison of orthologous regions confirms that all
measurable facets of higher order structure are conserved between human and
mouse, across the majority of the orthologous genome. This broad similarity is
observed in spite of the substantial time since the species diverged, differences in experimental procedures among the datasets examined, and the presence of cell
type specific structures at many loci. However, we also identify hundreds of regions showing consistent evidence of divergence between these species, constituting at least 10% of the orthologous mammalian genome and encompassing many
hundreds of human and mouse genes. Divergent regions are enriched in genes
implicated in vertebrate development, suggesting important roles for structural
divergence in mammalian evolution. They are also relatively enriched for genes
showing divergent expression patterns between human and mouse ES cells,
implying these regions may underlie divergent regulation. Divergent regions show
unusual shifts in compositional bias, sequence divergence and are unevenly
distributed across both genomes. We investigate the mechanisms of divergence in
higher order structure by examining the influence of sequence divergence and also
many features of primary level chromatin, such as histone modification and DNA
methylation patterns. Using multiple regression, we identify the dominant factors
that appear to have shaped the physical structure of the mammalian genome. These
data suggest that, though relatively rare, divergence in higher order chromatin
structure has played important roles during evolution
Mutational bias in spermatogonia impacts the anatomy of regulatory sites in the human genome
No full textATAC-Seq reports local chromatin accessibility and provides a snapshot of active regulatory regions and genomic regions occupied by DNA-binding proteins in a given tissue. We used ATAC-Seq to identify open chromatin sites in FGFR3-positive spermatogonial cells isolated from dissociated human testicular samples. FGFR3 is most highly expressed in self-renewing spermatogonial stem cells, with low expression also being detected in early differentiating spermatogonia; its expression thus overlaps with the onset of PRDM9 expression in pre-meiotic spermatogonia. Open chromatin in FGFR3-positive cells was identified using standard peak detection analysis with MACS2 software.Talmane, Lana; Kaiser, Vera; Kumar, Yatendra; Semple, Fiona; MacLennan, Marie; Semple, Colin; Fitzpatrick, David; Taylor, Martin. (2021). Mutational bias in spermatogonia impacts the anatomy of regulatory sites in the human genome, [dataset]. University of Edinburgh. MRC IGC. MRC Human Genetics Unit. https://doi.org/10.7488/ds/3053
Colin Fraser
No full textPhotograph - Colin Fraser (third from right) in a loaded scow leaving for Fort Chipewyan from Athabasca, Alberta. A group of men are also standing on the pie
Ribozyme catalysis with a twist: active state of the twister ribozyme in solution predicted from molecular simulation
No full textWe present results from molecular dynamics simulations and free energy calculations of the twister ribozyme at different stages along the reaction path to gain insight into its mechanism. The results, together with recent biochemical experiments, provide support for a mechanism involving general-acid catalysis by a conserved adenine residue in the active site. Although adenine has been previously implicated as a general acid acting through the N1 position in other ribozymes such as the hairpin and VS ribozymes, in the twister ribozyme there may be a twist. Biochemical experiments suggest that general acid catalysis may occur through the N3 position, which has never before been implicated in this role; however, currently, there is a lack of a detailed structural model for the active state of the twister ribozyme in solution that is consistent with these and other experiments. Simulations in a crystalline environment reported here are consistent with X-ray crystallographic data, and suggest that crystal packing contacts trap the RNA in an inactive conformation with U-1 in an extruded state that is incompatible with an in-line attack to the scissile phosphate. Simulations in solution, on the other hand, reveal this region to be dynamic and able to adopt a conformation where U-1 is stacked with G33. In this state, the nucleophile is in line with the scissile phosphate, and the N1 position of G33 and N3 position of A1 are poised to act as a general base and acid, respectively, as supported by mutational experiments. Free energy calculations further predict the electrostatic environment causes a shift of the microscopic pKa at the N3 position of A1 toward neutrality by approximately 5 pKa units. These results offer a unified interpretation of a broad range of currently available experimental data that points to a novel mode of general acid catalysis through the N3 position of an adenine nucleobase, thus expanding the repertoire of known mechanistic strategies employed by small nucleolytic ribozymes.Peer reviewe
Orbit design for future SpaceChip swarm missions in a planetary atmosphere
No full textThe effect of solar radiation pressure and atmospheric drag on the orbital dynamics of satellites-on-a-chip (SpaceChips) is exploited to design equatorial long-lived orbits about the oblate Earth. The orbit energy gain due to asymmetric solar radiation pressure, considering the Earth's shadow, is used to balance the energy loss due to atmospheric drag. Future missions for a swarm of SpaceChips are proposed, where a number of small devices are released from a conventional spacecraft to perform spatially distributed measurements of the conditions in the ionosphere and exosphere. It is shown that the orbit lifetime can be extended and indeed selected through solar radiation pressure and the end-of-life re-entry of the swarm can be ensured, by exploiting atmospheric drag
Inside which circle? A reply to Colin Bundy
No full textThe author contests Colin Bundy's recent characterisation of the inapplicability of colonialism of a special type theory to South Africa
Colin Woodard Reading & Book Signing
Full text linkJournalist, Colin Woodard, will do a reading and book signing on his new historical novel, The Republic of Pirates which tells the story of the Pirates of the Caribbean. Also author of The Lobster Coast, and Ocean\u27s End. Colin Woodard is native of Maine
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