ALBERT

Description: The nephrotoxic food mutagen ochratoxin A (OTA) produces DNA adducts in rat kidneys, the major lesion being the C8-linked-2'-deoxyguanosine adduct (OTB-dG). Although research on other adducts stresses the importance of understanding the structure of the associated adducted DNA, site-specific incorporation of OTB-dG into DNA has yet to be attempted. The present work uses a robust computational approach to determine the conformational preferences of OTB-dG in three ionization states at three guanine positions in the Nar I recognition sequence opposite cytosine. Representative adducted DNA helices were derived from over 2160 ns of simulation and ranked via free energies. For the first time, a close energetic separation between three distinct conformations is highlighted, which indicates OTA-adducted DNA likely adopts a mixture of conformations regardless of the sequence context. Nevertheless, the preferred conformation depends on the flanking bases and ionization state due to deviations in discrete local interactions at the lesion site. The structural characteristics of the lesion thus discerned have profound implications regarding its repair propensity and mutagenic outcomes, and support recent experiments suggesting the induction of double-strand breaks and deletion mutations upon OTA exposure. This combined structural and energetic characterization of the OTB-dG lesion in DNA will encourage future biochemical experiments on this potentially genotoxic lesion.

Description: Chelicerata represents one of the oldest groups of arthropods, with a fossil record extending to the Cambrian, and is sister group to the remaining extant arthropods, the mandibulates. Attempts to resolve the internal phylogeny of chelicerates have achieved little consensus, due to marked discord in both morphological and molecular hypotheses of chelicerate phylogeny. The monophyly of Arachnida, the terrestrial chelicerates, is generally accepted, but has garnered little support from molecular data, which have been limited either in breadth of taxonomic sampling or in depth of sequencing. To address the internal phylogeny of this group, we employed a phylogenomic approach, generating transcriptomic data for 17 species in combination with existing data, including two complete genomes. We analyzed multiple data sets containing up to 1,235,912 sites across 3,644 loci, using alternative approaches to optimization of matrix composition. Here, we show that phylogenetic signal for the monophyly of Arachnida is restricted to the 500 slowest-evolving genes in the data set. Accelerated evolutionary rates in Acariformes, Pseudoscorpiones, and Parasitiformes potentially engender long-branch attraction artifacts, yielding nonmonophyly of Arachnida with increasing support upon incrementing the number of concatenated genes. Mutually exclusive hypotheses are supported by locus groups of variable evolutionary rate, revealing significant conflicts in phylogenetic signal. Analyses of gene-tree discordance indicate marked incongruence in relationships among chelicerate orders, whereas derived relationships are demonstrably robust. Consistently recovered and supported relationships include the monophyly of Chelicerata, Euchelicerata, Tetrapulmonata, and all orders represented by multiple terminals. Relationships supported by subsets of slow-evolving genes include Ricinulei + Solifugae; a clade comprised of Ricinulei, Opiliones, and Solifugae; and a clade comprised of Tetrapulmonata, Scorpiones, and Pseudoscorpiones. We demonstrate that outgroup selection without regard for branch length distribution exacerbates long-branch attraction artifacts and does not mitigate gene-tree discordance, regardless of high gene representation for outgroups that are model organisms. Arachnopulmonata (new name) is proposed for the clade comprising Scorpiones + Tetrapulmonata (previously named Pulmonata).

Description: Cool cluster cores are in global thermal equilibrium but are locally thermally unstable. We study a non-linear phenomenological model for the evolution of density perturbations in the intracluster medium (ICM) due to local thermal instability and gravity. We have analysed and extended a model for the evolution of an overdense blob in the ICM. We find two regimes in which the overdense blobs can cool to thermally stable low temperatures. One for large t cool / t ff ( t cool is the cooling time and t ff is the free-fall time), where a large initial overdensity is required for thermal runaway to occur; this is the regime which was previously analysed in detail. We discover a second regime for t cool / t ff 1 (in agreement with Cartesian simulations of local thermal instability in an external gravitational field), where runaway cooling happens for arbitrarily small amplitudes. Numerical simulations have shown that cold gas condenses out more easily in a spherical geometry. We extend the analysis to include geometrical compression in weakly stratified atmospheres such as the ICM. With a single parameter, analogous to the mixing length, we are able to reproduce the results from numerical simulations; namely, small density perturbations lead to the condensation of extended cold filaments only if t cool / t ff 10.

Description: Chemical mutagens with an aromatic ring system may be enzymatically transformed to afford aryl radical species that preferentially react at the C8-site of 2'-deoxyguanosine (dG). The resulting carbon-linked C8-aryl-dG adduct possesses altered biophysical and genetic coding properties compared to the precursor nucleoside. Described herein are structural and in vitro mutagenicity studies of a series of fluorescent C8-aryl-dG analogues that differ in aryl ring size and are representative of authentic DNA adducts. These structural mimics have been inserted into a hotspot sequence for frameshift mutations, namely, the reiterated G 3 -position of the Nar I sequence within 12mer ( Nar I(12)) and 22mer ( Nar I(22)) oligonucleotides. In the Nar I(12) duplexes, the C8-aryl-dG adducts display a preference for adopting an anti -conformation opposite C, despite the strong syn preference of the free nucleoside. Using the Nar I(22) sequence as a template for DNA synthesis in vitro , mutagenicity of the C8-aryl-dG adducts was assayed with representative high-fidelity replicative versus lesion bypass Y-family DNA polymerases, namely, Escherichia coli pol I Klenow fragment exo – (Kf – ) and Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4). Our experiments provide a basis for a model involving a two-base slippage and subsequent realignment process to relate the miscoding properties of C-linked C8-aryl-dG adducts with their chemical structures.

Description: We study the interplay between turbulent heating, mixing, and radiative cooling in an idealized model of cool cluster cores. Active galactic nuclei (AGN) jets are expected to drive turbulence and heat cluster cores. Cooling of the intracluster medium (ICM) and stirring by AGN jets are tightly coupled in a feedback loop. We impose the feedback loop by balancing radiative cooling with turbulent heating. In addition to heating the plasma, turbulence also mixes it, suppressing the formation of cold gas at small scales. In this regard, the effect of turbulence is analogous to thermal conduction. For uniform plasma in thermal balance (turbulent heating balancing radiative cooling), cold gas condenses only if the cooling time is shorter than the mixing time. This condition requires the turbulent kinetic energy to be the plasma internal energy; such high velocities in cool cores are ruled out by observations. The results with realistic magnetic fields and thermal conduction are qualitatively similar to the hydrodynamic simulations. Simulations where the runaway cooling of the cool core is prevented due to mixing with the hot ICM show cold gas even with subsonic turbulence, consistent with observations. Thus, turbulent mixing is the likely mechanism via which AGN jets heat cluster cores. The thermal instability growth rates observed in simulations with turbulence are consistent with the local thermal instability interpretation of cold gas in cluster cores.

Description: We study the conditions for disc galaxies to produce superbubbles that can break out of the disc and produce a galactic wind. We argue that the threshold surface density of supernovae rate for seeding a wind depends on the ability of superbubble energetics to compensate for radiative cooling. We first adapt Kompaneets formalism for expanding bubbles in a stratified medium to the case of continuous energy injection and include the effects of radiative cooling in the shell. With the help of hydrodynamic simulations, we then study the evolution of superbubbles evolving in stratified discs with typical disc parameters. We identify two crucial energy injection rates that differ in their effects, the corresponding breakout ranging from being gentle to a vigorous one. (a) Superbubbles that break out of the disc with a Mach number of the order of 2–3 correspond to an energy injection rate of the order of 10 –4 erg cm –2  s –1 , which is relevant for disc galaxies with synchrotron emitting gas in the extra-planar regions. (b) A larger energy injection threshold, of the order of 10 –3 erg cm –2  s –1 , or equivalently, a star formation surface density of ~0.1 M yr –1 kpc –2 , corresponds to superbubbles with a Mach number ~5–10. While the milder superbubbles can be produced by large OB associations, the latter kind requires super-starclusters. These derived conditions compare well with observations of disc galaxies with winds and the existence of multiphase halo gas. Furthermore, we find that contrary to the general belief that superbubbles fragment through Rayleigh–Taylor (RT) instability when they reach a vertical height of the order of the scaleheight, the superbubbles are first affected by thermal instability for typical disc parameters and that RT instability takes over when the shells reach a distance of approximately twice the scaleheight.

Description: Using idealized one-dimensional Eulerian hydrodynamic simulations, we contrast the behaviour of isolated supernovae with the superbubbles driven by multiple, collocated supernovae. Continuous energy injection via successive supernovae exploding within the hot/dilute bubble maintains a strong termination shock. This strong shock keeps the superbubble overpressured and drives the outer shock well after it becomes radiative. Isolated supernovae, in contrast, with no further energy injection, become radiative quite early (0.1 Myr, tens of pc), and stall at scales 100 pc. We show that isolated supernovae lose almost all of their mechanical energy by 1 Myr, but superbubbles can retain up to ~40 per cent of the input energy in the form of mechanical energy over the lifetime of the star cluster (a few tens of Myr). These conclusions hold even in the presence of realistic magnetic fields and thermal conduction. We also compare various methods for implementing supernova feedback in numerical simulations. For various feedback prescriptions, we derive the spatial scale below which the energy needs to be deposited in order for it to couple to the interstellar medium. We show that a steady thermal wind within the superbubble appears only for a large number (10 4 ) of supernovae. For smaller clusters, we expect multiple internal shocks instead of a smooth, dense thermalized wind.

Description: We perform global linear stability analysis and idealized numerical simulations in global thermal balance to understand the condensation of cold gas from hot/virial atmospheres (coronae), in particular the intracluster medium (ICM). We pay particular attention to geometry (e.g. spherical versus plane-parallel) and the nature of the gravitational potential. Global linear analysis gives a similar value for the fastest growing thermal instability modes in spherical and Cartesian geometries. Simulations and observations suggest that cooling in haloes critically depends on the ratio of the cooling time to the free-fall time ( t cool / t ff ). Extended cold gas condenses out of the ICM only if this ratio is smaller than a threshold value close to 10. Previous works highlighted the difference between the nature of cold gas condensation in spherical and plane-parallel atmospheres; namely, cold gas condensation appeared easier in spherical atmospheres. This apparent difference due to geometry arises because the previous plane-parallel simulations focused on in situ condensation of multiphase gas but spherical simulations studied condensation anywhere in the box. Unlike previous claims, our non-linear simulations show that there are only minor differences in cold gas condensation, either in situ or anywhere, for different geometries. The amount of cold gas depends on the shape of t cool / t ff ; gas has more time to condense if gravitational acceleration decreases towards the centre. In our idealized plane-parallel simulations with heating balancing cooling in each layer, there can be significant mass/energy/momentum transfer across layers that can trigger condensation and drive t cool / t ff far beyond the critical value close to 10.

Description: Motivation: Influenza is responsible for half a million deaths annually, and vaccination is the best preventive measure against this pervasive health problem. Influenza vaccines developed from surveillance data of each season are strain-specific, and therefore, are unable to provide protection against pandemic strains arising from antigenic shift and drift. Seasonal epidemics and occasional pandemics of influenza have created a need for a universal influenza vaccine (UIV). Researchers have shown that a combination of conserved epitopes has the potential to be used as a UIV. Result: In the present work, available data on strains, proteins, epitopes and their associated information were used to develop a Web resource, ‘EpiCombFlu’, which can explore different influenza epitopes and their combinations for conservation among different strains, population coverage and immune response for vaccine design. Forward selection algorithm was implemented in EpiCombFlu to select optimum combination of epitopes that may be expressed and evaluated as potential UIV. Availability: The Web resource is freely available at http://117.211.115.67/influenza/home.html . Contact: chittaranjan.rout@juit.ac.in Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Energetic winds and radiation from massive star clusters push the surrounding gas and blow superbubbles in the interstellar medium (ISM). Using 1D hydrodynamic simulations, we study the role of radiation in the dynamics of superbubbles driven by a young star cluster of mass 10 6 M . We have considered a realistic time evolution of the mechanical power as well as radiation power of the star cluster, and detailed heating and cooling processes. We find that the ratio of the radiation pressure on the shell (shocked ISM) to the thermal pressure (~10 7  K) of the shocked-wind region is almost independent of the ambient density, and it is greater than unity before 1 Myr. We explore the parameter space of density and dust opacity of the ambient medium, and find that the size of the hot gas (~10 7  K) cavity is insensitive to the dust opacity [ d (0.1–1.5) x 10 –21  cm 2 ], but the structure of the photoionized (~10 4  K) gas depends on it. Most of the radiative losses occur at ~10 4  K, with sub-dominant losses at 10 3  K and ~10 6 –10 8  K. The superbubbles can retain as high as ~10 per cent of its input energy, for an ambient density of 10 3 m H cm –3 . We discuss the role of ionization parameter and recombination-averaged density in understanding the dominant feedback mechanism. Finally, we compare our results with the observations of 30 Doradus.