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  • Oxford University Press  (78,388)
  • Periodicals Archive Online (PAO)
  • Public Library of Science (PLoS)
  • 2010-2014  (105,068)
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  • 1
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    Post-seismic viscoelastic deformation and stress transfer after the 1960 M9.5 Valdivia, Chile earthquake : effects on the 2010 M8.8 Maule, Chile earthquake (2014)
    Oxford University Press
    Details
    Publication Date: 2022-05-25
    Description: Author Posting. © The Authors, 2014. This article is posted here by permission of The Royal Astronomical Society for personal use, not for redistribution. The definitive version was published in Geophysical Journal International 197 (2014): 697-704, doi:10.1093/gji/ggu048.
    Description: After the 1960 M9.5 Valdivia, Chile earthquake, three types of geodetic observations were made during four time periods at nearby locations. These post-seismic observations were previously explained by post-seismic afterslip on the downdip extension of the 1960 rupture plane. In this study, we demonstrate that the post-seismic observations can be explained alternatively by volumetric viscoelastic relaxation of the asthenosphere mantle. In searching for the best-fitting viscosity model, we invert for two variables, the thickness of the elastic lithosphere, He, and the effective Maxwell decay time of the asthenosphere mantle, TM, assuming a 100-km-thick asthenosphere mantle. The best solutions to fit the observations in four sequential time periods, 1960–1964, 1960–1968, 1965–1973 and 1980–2010, each yield a similar He value of about 65 km but significantly increasing TM values of 0.7, 6, 10 and 80 yr, respectively. We calculate the corresponding viscoelastic Coulomb stress increase since 1960 on the future rupture plane of the 2010 M8.8 Maule, Chile earthquake. The calculated viscoelastic stress increase on the 2010 rupture plane varies gradually from 13.1 bars at the southern end to 0.1 bars at the northern end. In contrast, the stress increase caused by an afterslip model has a similar spatial distribution but slightly smaller values of 0.1–3.2 bars on the 2010 rupture plane.
    Description: This work was supported by a MIT/WHOI Joint Program Student Fellowship and a Graduate Student Fellowship from the WHOI Deep Ocean Exploration Institute (MD), as well as NSF Grant OCE-1141785 and a Deerbrook Foundation Award (JL).
    Keywords: Seismic cycle ; Transient deformation ; Seismicity and tectonics ; Subduction zone processes ; Dynamics: seismotectonics ; South America
    Repository Name: Woods Hole Open Access Server
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  • 2
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    Horizontal gene transfer is a significant driver of gene innovation in dinoflagellates (2014)
    Oxford University Press
    Details
    Publication Date: 2022-05-26
    Description: © The Author(s), 2013. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Genome Biology and Evolution 5 (2013): 2368-2381, doi:10.1093/gbe/evt179.
    Description: The dinoflagellates are an evolutionarily and ecologically important group of microbial eukaryotes. Previous work suggests that horizontal gene transfer (HGT) is an important source of gene innovation in these organisms. However, dinoflagellate genomes are notoriously large and complex, making genomic investigation of this phenomenon impractical with currently available sequencing technology. Fortunately, de novo transcriptome sequencing and assembly provides an alternative approach for investigating HGT. We sequenced the transcriptome of the dinoflagellate Alexandrium tamarense Group IV to investigate how HGT has contributed to gene innovation in this group. Our comprehensive A. tamarense Group IV gene set was compared with those of 16 other eukaryotic genomes. Ancestral gene content reconstruction of ortholog groups shows that A. tamarense Group IV has the largest number of gene families gained (314–1,563 depending on inference method) relative to all other organisms in the analysis (0–782). Phylogenomic analysis indicates that genes horizontally acquired from bacteria are a significant proportion of this gene influx, as are genes transferred from other eukaryotes either through HGT or endosymbiosis. The dinoflagellates also display curious cases of gene loss associated with mitochondrial metabolism including the entire Complex I of oxidative phosphorylation. Some of these missing genes have been functionally replaced by bacterial and eukaryotic xenologs. The transcriptome of A. tamarense Group IV lends strong support to a growing body of evidence that dinoflagellate genomes are extraordinarily impacted by HGT.
    Description: J.H.W. was supported by the NSF IGERT Program in Comparative Genomics at the University of Arizona (grant number DGE-0654435). This work was supported by grants from the National Science Foundation (grant numbers OCE-0723498, EF-0732440) and funding provided by the BIO5 Institute at the University of Arizona to J.D.H.
    Keywords: Gene innovation ; Alexandrium tamarense Group IV ; Phylogenetic profile ; Phylogenomics ; De novo transcriptome assembly ; Mitochondrial metabolism
    Repository Name: Woods Hole Open Access Server
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  • 3
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    Magnetotelluric data, stable distributions and impropriety: an existential combination (2014)
    Oxford University Press
    Details
    Publication Date: 2022-05-26
    Description: Author Posting. © Author, 2014. This article is posted here by permission of The Royal Astronomical Society for personal use, not for redistribution. The definitive version was published in Geophysical Journal International 198 (2014): 622-636, doi: 10.1093/gji/ggu121.
    Description: The robust statistical model of a Gaussian core contaminated by outlying data that underlies robust estimation of the magnetotelluric (MT) response function has been re-examined. The residuals from robust estimators are systematically long tailed compared to a distribution based on the Gaussian, and hence are inconsistent with the robust model. Instead, MT data are pervasively described by the alpha stable distribution family whose variance and sometimes mean are undefined. A maximum likelihood estimator (MLE) that exploits the stable nature of MT data is formulated, and its two-stage implementation in which stable parameters are first fit to the data and then the MT responses are solved for is described. The MLE is shown to be inherently robust, but differs from the conventional robust estimator because it is based on a model derived from the data, while robust estimators are ad hoc, being based on the robust model that is inconsistent with actual data. Propriety versus impropriety of the complex MT response was investigated, and a likelihood ratio test for propriety and its null distribution was established. The Cramér-Rao lower bounds for the covariance matrix of proper and improper MT responses were specified. The MLE was applied to exemplar long period and broad-band data sets from South Africa. Both are shown to be significantly stably distributed using the Kolmogorov–Smirnov goodness of fit and Ansari-Bradley non-parametric dispersion tests. Impropriety of the MT responses at both sites is pervasive, hence the improper Cramér-Rao bound was used to estimate the MLE covariance. The MLE is shown to be nearly unbiased and well described by a Gaussian distribution based on bootstrap simulation. The MLE was compared to a conventional robust estimator, establishing that the standard errors of the former are systematically smaller than for the latter and that the standardized differences between them exhibit excursions that are both too frequent and too large to be described by a Gaussian model. This is ascribed to pervasive bias of the robust estimator that is to some degree obscured by their systematically large confidence bounds. Finally, a series of topics for further investigation is proposed.
    Description: This work was supported by NSF grant EAR0809074.
    Keywords: Time series analysis ; Numerical approximations and analysis ; Fractals and multifractals ; Probability distributions ; Magnetotellurics
    Repository Name: Woods Hole Open Access Server
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  • 4
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    Virus infection of Haptolina ericina and Phaeocystis pouchetii implicates evolutionary conservation of programmed cell death induction in marine haptophyte–virus interactions (2014)
    Oxford University Press
    Details
    Publication Date: 2022-05-26
    Description: © The Author(s), 2014. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Journal of Plankton Research 36 (2014): 943-955, doi:10.1093/plankt/fbu029.
    Description: The mechanisms by which phytoplankton cope with stressors in the marine environment are neither fully characterized nor understood. As viruses are the most abundant entities in the global ocean and represent a strong top-down regulator of phytoplankton abundance and diversity, we sought to characterize the cellular response of two marine haptophytes to virus infection in order to gain more knowledge about the nature and diversity of microalgal responses to this chronic biotic stressor. We infected laboratory cultures of the haptophytes Haptolina ericina and Phaeocystis pouchetii with CeV-01B or PpV-01B dsDNA viruses, respectively, and assessed the extent to which host cellular responses resemble programmed cell death (PCD) through the activation of diagnostic molecular and biochemical markers. Pronounced DNA fragmentation and activation of cysteine aspartate-specific proteases (caspases) were only detected in virus-infected cultures of these phytoplankton. Inhibition of host caspase activity by addition of the pan-caspase inhibitor z-VAD-fmk did not impair virus production in either host–virus system, differentiating it from the Emiliania huxleyi-Coccolithovirus model of haptophyte–virus interactions. Nonetheless, our findings point to a general conservation of PCD-like activation during virus infection in ecologically diverse haptophytes, with the subtle heterogeneity of cell death biochemical responses possibly exerting differential regulation on phytoplankton abundance and diversity.
    Description: Funding to J.L.R, R.-A.S. and A.L. was provided by the Norwegian Research Council for the “VIPMAP” (nr. 186142) and “HAPTODIV” (nr. 190307) projects, and by the European Research Council Advanced Grant ERC-AG-LS8 “Microbial Network Organisation” (MINOS, project number 250254). J.L.R. received a FRIBIO overseas research fellowship from the Norwegian Research Council. K.D.B. and B.V.M. were supported by funding from the United States National Science Foundation (OCE-1061883).
    Keywords: Caspase ; DNA fragmentation ; IETD ; Phycodnaviridae ; z-VAD-fmk ; Haptophyte
    Repository Name: Woods Hole Open Access Server
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  • 5
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    The evolution of the four subunits of voltage-gated calcium channels : ancient roots, increasing complexity, and multiple losses (2014)
    Oxford University Press
    Details
    Publication Date: 2022-05-26
    Description: © The Author(s), 2014. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Genome Biology and Evolution 6 (2014): 2210-2217, doi:10.1093/gbe/evu177.
    Description: The alpha subunits of voltage-gated calcium channels (Cavs) are large transmembrane proteins responsible for crucial physiological processes in excitable cells. They are assisted by three auxiliary subunits that can modulate their electrical behavior. Little is known about the evolution and roles of the various subunits of Cavs in nonbilaterian animals and in nonanimal lineages. For this reason, we mapped the phyletic distribution of the four channel subunits and reconstructed their phylogeny. Although alpha subunits have deep evolutionary roots as ancient as the split between plants and opistokonths, beta subunits appeared in the last common ancestor of animals and their close-relatives choanoflagellates, gamma subunits are a bilaterian novelty and alpha2/delta subunits appeared in the lineage of Placozoa, Cnidaria, and Bilateria. We note that gene losses were extremely common in the evolution of Cavs, with noticeable losses in multiple clades of subfamilies and also of whole Cav families. As in vertebrates, but not protostomes, Cav channel genes duplicated in Cnidaria. We characterized by in situ hybridization the tissue distribution of alpha subunits in the sea anemone Nematostella vectensis, a nonbilaterian animal possessing all three Cav subfamilies common to Bilateria. We find that some of the alpha subunit subtypes exhibit distinct spatiotemporal expression patterns. Further, all six sea anemone alpha subunit subtypes are conserved in stony corals, which separated from anemones 500 MA. This unexpected conservation together with the expression patterns strongly supports the notion that these subtypes carry unique functional roles.
    Keywords: Voltage-gated calcium channel ; Ion channel ; Cnidaria ; Nematostella vectensis ; Evolution of nervous system
    Repository Name: Woods Hole Open Access Server
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  • 6
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    Cyberdiversity: Improving the Informatic Value of Diverse Tropical Arthropod Inventories (2014)
    Public Library of Science (PLoS)
    In:  PLoS ONE vol. 9 no. 12, pp. e115750-e115750
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    Publication Date: 2024-01-12
    Keywords: Multidisciplinary
    Repository Name: National Museum of Natural History, Netherlands
    Type: info:eu-repo/semantics/article
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  • 7
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    Multi-events earthquake early warning algorithm using a Bayesian approach (2014)
    Oxford University Press
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    Publication Date: 2014-12-13
    Description: Current earthquake early warning (EEW) systems lack the ability to appropriately handle multiple concurrent earthquakes, which led to many false alarms during the 2011 Tohoku earthquake sequence in Japan. This paper uses a Bayesian probabilistic approach to handle multiple concurrent events for EEW. We implement the theory using a two-step algorithm. First, an efficient approximate Bayesian model class selection scheme is used to estimate the number of concurrent events. Then, the Rao-Blackwellized Importance Sampling method with a sequential proposal probability density function is used to estimate the earthquake parameters, that is hypocentre location, origin time, magnitude and local seismic intensity. A real data example based on 2 months data (2011 March 9–April 30) around the time of the 2011 M 9 Tohoku earthquake is studied to verify the proposed algorithm. Our algorithm results in over 90 per cent reduction in the number of incorrect warnings compared to the existing EEW system operating in Japan.
    Keywords: Seismology
    Print ISSN: 0956-540X
    Electronic ISSN: 1365-246X
    Topics: Geosciences
    Published by Oxford University Press on behalf of The Deutsche Geophysikalische Gesellschaft (DGG) and the Royal Astronomical Society (RAS).
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  • 8
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    Extensive Copy Number Variations in Admixed Indian Population of African Ancestry: Potential Involvement in Adaptation (2014)
    Oxford University Press
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    Publication Date: 2014-12-13
    Description: Admixture mapping has been enormously resourceful in identifying genetic variations linked to phenotypes, adaptation, and diseases. In this study through analysis of copy number variable regions (CNVRs), we report extensive restructuring in the genomes of the recently admixed African-Indian population (OG-W-IP) that inhabits a highly saline environment in Western India. The study included subjects from OG-W-IP (OG), five different Indian and three HapMap populations that were genotyped using Affymetrix version 6.0 arrays. Copy number variations (CNVs) detected using Birdsuite were used to define CNVRs. Population structure with respect to CNVRs was delineated using random forest approach. OG genomes have a surprising excess of CNVs in comparison to other studied populations. Individual ancestry proportions computed using STRUCTURE also reveals a unique genetic component in OGs. Population structure analysis with CNV genotypes indicates OG to be distant from both the African and Indian ancestral populations. Interestingly, it shows genetic proximity with respect to CNVs to only one Indian population IE-W-LP4, which also happens to reside in the same geographical region. We also observe a significant enrichment of molecular processes related to ion binding and receptor activity in genes encompassing OG-specific CNVRs. Our results suggest that retention of CNVRs from ancestral natives and de novo acquisition of CNVRs could accelerate the process of adaptation especially in an extreme environment. Additionally, this population would be enormously useful for dissecting genes and delineating the involvement of CNVs in salt adaptation.
    Electronic ISSN: 1759-6653
    Topics: Biology
    Published by Oxford University Press
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  • 9
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    A catalogue of 2D photometric decompositions in the SDSS-DR7 spectroscopic main galaxy sample: preferred models and systematics (2014)
    Oxford University Press
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    Publication Date: 2014-12-12
    Description: We present a catalogue of 2D, point spread function-corrected de Vacouleurs, Sérsic, de Vacouleurs+Exponential, and Sérsic+Exponential fits of ~7 x 10 5 spectroscopically selected galaxies drawn from the Sloan Digital Sky Survey (SDSS) Data Release 7. Fits are performed for the SDSS r band utilizing the fitting routine galfit and analysis pipeline pymorph . We compare these fits to prior catalogues. Fits are analysed using a physically motivated flagging system. The flags suggest that more than 90 per cent of two-component fits can be used for analysis. We show that the fits follow the expected behaviour for early and late galaxy types. The catalogues provide a robust set of structural and photometric parameters for future galaxy studies. We show that some biases remain in the measurements, e.g. the presence of bars significantly affect the bulge measurements although the bulge ellipticity may be used to separate barred and non-barred galaxies, and about 15 per cent of bulges of two-component fits are also affected by resolution. The catalogues are available in electronic format. We also provide an interface for generating postage stamp images of the 2D model and residual as well as the 1D profile. These images can be generated for a user-uploaded list of galaxies on demand.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 10
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    Unisexual Reproduction Drives Meiotic Recombination and Phenotypic and Karyotypic Plasticity in Cryptococcus neoformans (2014)
    Public Library of Science (PLoS)
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    Publication Date: 2014-12-12
    Description: by Sheng Sun, R. Blake Billmyre, Piotr A. Mieczkowski, Joseph Heitman In fungi, unisexual reproduction, where sexual development is initiated without the presence of two compatible mating type alleles, has been observed in several species that can also undergo traditional bisexual reproduction, including the important human fungal pathogens Cryptococcus neoformans and Candida albicans . While unisexual reproduction has been well characterized qualitatively, detailed quantifications are still lacking for aspects of this process, such as the frequency of recombination during unisexual reproduction, and how this compares with bisexual reproduction. Here, we analyzed meiotic recombination during α-α unisexual and a-α bisexual reproduction of C. neoformans . We found that meiotic recombination operates in a similar fashion during both modes of sexual reproduction. Specifically, we observed that in α-α unisexual reproduction, the numbers of crossovers along the chromosomes during meiosis, recombination frequencies at specific chromosomal regions, as well as meiotic recombination hot and cold spots, are all similar to those observed during a-α bisexual reproduction. The similarity in meiosis is also reflected by the fact that phenotypic segregation among progeny collected from the two modes of sexual reproduction is also similar, with transgressive segregation being observed in both. Additionally, we found diploid meiotic progeny were also produced at similar frequencies in the two modes of sexual reproduction, and transient chromosomal loss and duplication likely occurs frequently and results in aneuploidy and loss of heterozygosity that can span entire chromosomes. Furthermore, in both α-α unisexual and a-α bisexual reproduction, we observed biased allele inheritance in regions on chromosome 4, suggesting the presence of fragile chromosomal regions that might be vulnerable to mitotic recombination. Interestingly, we also observed a crossover event that occurred within the MAT locus during α-α unisexual reproduction. Our results provide definitive evidence that α-α unisexual reproduction is a meiotic process similar to a-α bisexual reproduction.
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
    Topics: Biology
    Published by Public Library of Science (PLoS)
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  • 11
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    Echoes of the Past: Hereditarianism and A Troublesome Inheritance (2014)
    Public Library of Science (PLoS)
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    Publication Date: 2014-12-12
    Description: by Marcus Feldman
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
    Topics: Biology
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  • 12
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    The miR9863 Family Regulates Distinct Mla Alleles in Barley to Attenuate NLR Receptor-Triggered Disease Resistance and Cell-Death Signaling (2014)
    Public Library of Science (PLoS)
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    Publication Date: 2014-12-12
    Description: by Jie Liu, Xiliu Cheng, Da Liu, Weihui Xu, Roger Wise, Qian-Hua Shen Barley ( Hordeum vulgare L.) Mla alleles encode coiled-coil (CC), nucleotide binding, leucine-rich repeat (NB-LRR) receptors that trigger isolate-specific immune responses against the powdery mildew fungus, Blumeria graminis f. sp. hordei ( Bgh ). How Mla or NB-LRR genes in grass species are regulated at post-transcriptional level is not clear. The microRNA family, miR9863, comprises four members that differentially regulate distinct Mla alleles in barley. We show that miR9863 members guide the cleavage of Mla1 transcripts in barley, and block or reduce the accumulation of MLA1 protein in the heterologous Nicotiana benthamiana expression system. Regulation specificity is determined by variation in a unique single-nucleotide-polymorphism (SNP) in mature miR9863 family members and two SNPs in the Mla miR9863-binding site that separates these alleles into three groups. Further, we demonstrate that 22-nt miR9863s trigger the biogenesis of 21-nt phased siRNAs (phasiRNAs) and together these sRNAs form a feed-forward regulation network for repressing the expression of group I Mla alleles. Overexpression of miR9863 members specifically attenuates MLA1, but not MLA10-triggered disease resistance and cell-death signaling. We propose a key role of the miR9863 family in dampening immune response signaling triggered by a group of MLA immune receptors in barley.
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
    Topics: Biology
    Published by Public Library of Science (PLoS)
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  • 13
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    Global Analysis of Photosynthesis Transcriptional Regulatory Networks (2014)
    Public Library of Science (PLoS)
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    Publication Date: 2014-12-12
    Description: by Saheed Imam, Daniel R. Noguera, Timothy J. Donohue Photosynthesis is a crucial biological process that depends on the interplay of many components. This work analyzed the gene targets for 4 transcription factors: FnrL, PrrA, CrpK and MppG (RSP_2888), which are known or predicted to control photosynthesis in Rhodobacter sphaeroides . Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) identified 52 operons under direct control of FnrL, illustrating its regulatory role in photosynthesis, iron homeostasis, nitrogen metabolism and regulation of sRNA synthesis. Using global gene expression analysis combined with ChIP-seq, we mapped the regulons of PrrA, CrpK and MppG. PrrA regulates ∼34 operons encoding mainly photosynthesis and electron transport functions, while CrpK, a previously uncharacterized Crp-family protein, regulates genes involved in photosynthesis and maintenance of iron homeostasis. Furthermore, CrpK and FnrL share similar DNA binding determinants, possibly explaining our observation of the ability of CrpK to partially compensate for the growth defects of a ΔFnrL mutant. We show that the Rrf2 family protein, MppG, plays an important role in photopigment biosynthesis, as part of an incoherent feed-forward loop with PrrA. Our results reveal a previously unrealized, high degree of combinatorial regulation of photosynthetic genes and significant cross-talk between their transcriptional regulators, while illustrating previously unidentified links between photosynthesis and the maintenance of iron homeostasis.
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
    Topics: Biology
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  • 14
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    The nphp-2 and arl-13 Genetic Modules Interact to Regulate Ciliogenesis and Ciliary Microtubule Patterning in C. elegans (2014)
    Public Library of Science (PLoS)
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    Publication Date: 2014-12-12
    Description: by Simon R. F. Warburton-Pitt, Malan Silva, Ken C. Q. Nguyen, David H. Hall, Maureen M. Barr Cilia are microtubule-based cellular organelles that mediate signal transduction. Cilia are organized into several structurally and functionally distinct compartments: the basal body, the transition zone (TZ), and the cilia shaft. In vertebrates, the cystoprotein Inversin localizes to a portion of the cilia shaft adjacent to the TZ, a region termed the “Inversin compartment” (InvC). The mechanisms that establish and maintain the InvC are unknown. In the roundworm C. elegans, the cilia shafts of amphid channel and phasmid sensory cilia are subdivided into two regions defined by different microtubule ultrastructure: a proximal doublet-based region adjacent to the TZ, and a distal singlet-based region. It has been suggested that C. elegans cilia also possess an InvC, similarly to mammalian primary cilia. Here we explored the biogenesis, structure, and composition of the C. elegans ciliary doublet region and InvC. We show that the InvC is conserved and distinct from the doublet region. nphp-2 (the C. elegans Inversin homolog) and the doublet region genes arl-13 , klp-11, and unc-119 are redundantly required for ciliogenesis. InvC and doublet region genes can be sorted into two modules— nphp-2 + klp-11 and arl-13 + unc-119— which are both antagonized by the hdac-6 deacetylase. The genes of this network modulate the sizes of the NPHP-2 InvC and ARL-13 doublet region. Glutamylation, a tubulin post-translational modification, is not required for ciliary targeting of InvC and doublet region components; rather, glutamylation is modulated by nphp-2 , arl-13 , and unc-119 . The ciliary targeting and restricted localization of NPHP-2, ARL-13, and UNC-119 does not require TZ-, doublet region, and InvC-associated genes. NPHP-2 does require its calcium binding EF hand domain for targeting to the InvC. We conclude that the C. elegans InvC is distinct from the doublet region, and that components in these two regions interact to regulate ciliogenesis via cilia placement, ciliary microtubule ultrastructure, and protein localization.
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
    Topics: Biology
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  • 15
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    Unexpected DNA Loss Mediated by the DNA Binding Activity of Ribonuclease A (2014)
    Public Library of Science (PLoS)
    In: PLoS ONE
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    Publication Date: 2014-12-12
    Description: by Federico Donà, Jonathan Houseley Ribonuclease A (RNase A) is widely used in molecular biology research both for analytical assays and for nucleic acid preparation. The catalytic mechanism of RNase A is well understood and absolutely precludes activity on DNA; however anecdotal reports of DNA degradation by RNase A are not uncommon. Here we describe a mechanism by which RNase A treatment can lead to apparent DNA degradation. This results from the surprising finding that RNase A remains functional in a phenol:chloroform mixture, to our knowledge the only enzyme that survives this highly denaturing solvent environment. Although RNase A does not cleave the DNA backbone it is capable of binding to DNA, forming stable RNase A-DNA complexes that partition to the interphase or organic phase during phenol:chloroform purification. The unexpected survival of the RNase A DNA-binding activity in phenol means that these complexes are not dissolved and a substantial amount of RNase A-bound DNA is permanently removed from the aqueous phase and lost on phase separation. This effect will impact DNA recovery from multiple procedures and is likely to represent a source of sequence bias in genome-wide studies. Our results also indicate that the results of analytical studies performed using RNase A must be considered with care.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 16
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    Screening for Vulnerability in Older Cancer Patients: The ONCODAGE Prospective Multicenter Cohort Study (2014)
    Public Library of Science (PLoS)
    In: PLoS ONE
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    Publication Date: 2014-12-12
    Description: by Pierre Soubeyran, Carine Bellera, Jean Goyard, Damien Heitz, Hervé Curé, Hubert Rousselot, Gilles Albrand, Véronique Servent, Olivier Saint Jean, Isabelle van Praagh, Jean-Emmanuel Kurtz, Stéphane Périn, Jean-Luc Verhaeghe, Catherine Terret, Christophe Desauw, Véronique Girre, Cécile Mertens, Simone Mathoulin-Pélissier, Muriel Rainfray Background Geriatric Assessment is an appropriate method for identifying older cancer patients at risk of life-threatening events during therapy. Yet, it is underused in practice, mainly because it is time- and resource-consuming. This study aims to identify the best screening tool to identify older cancer patients requiring geriatric assessment by comparing the performance of two short assessment tools the G8 and the Vulnerable Elders Survey (VES-13). Patients and Methods The diagnostic accuracy of the G8 and the (VES-13) were evaluated in a prospective cohort study of 1674 cancer patients accrued before treatment in 23 health care facilities. 1435 were eligible and evaluable. Outcome measures were multidimensional geriatric assessment (MGA), sensitivity (primary), specificity, negative and positive predictive values and likelihood ratios of the G8 and VES-13, and predictive factors of 1-year survival rate. Results Patient median age was 78.2 years (70-98) with a majority of females (69.8%), various types of cancer including 53.9% breast, and 75.8% Performance Status 0-1. Impaired MGA, G8, and VES-13 were 80.2%, 68.4%, and 60.2%, respectively. Mean time to complete G8 or VES-13 was about five minutes. Reproducibility of the two questionnaires was good. G8 appeared more sensitive (76.5% versus 68.7%, P  =  0.0046) whereas VES-13 was more specific (74.3% versus 64.4%, P
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 17
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    Impact of the Lab-Score on Antibiotic Prescription Rate in Children with Fever without Source: A Randomized Controlled Trial (2014)
    Public Library of Science (PLoS)
    In: PLoS ONE
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    Publication Date: 2014-12-12
    Description: by Laurence Lacroix, Sergio Manzano, Lynda Vandertuin, Florence Hugon, Annick Galetto-Lacour, Alain Gervaix Background The Lab-score, based on the combined determination of procalcitonin, C-reactive protein and urinary dipstick results, has been shown accurate in detecting serious bacterial infections (SBI) in children with fever without source (FWS) on retrospective cohorts. We aimed to prospectively assess the utility of the Lab-score in safely decreasing antibiotic prescriptions in children with FWS and to determine its diagnostic characteristics compared to common SBI biomarkers. Methods Randomized controlled trial in children 7 days to 36 months old with FWS, allocated either to the Lab-score group (Lab-score reported, blinded WBC count) or to the control group (WBC, bands and C-reactive protein determined, blinded procalcitonin and Lab-score), followed up until recovery. Demographic data, antibiotic prescription rate, admission rate and diagnostic properties of the Lab-score were analyzed. Results 271 children were analyzed. No statistically significant difference concerning antibiotic prescription rate was observed: 41.2% (54 of 131) in the Lab-score group and 42.1% (59 of 140) in the control group (p = 1.000). If recommendations based on the Lab-score had been strictly applied, a hypothetical 30.6% treatment rate would have been encountered, compared to the overall 41.7% observed rate (p = 0.0095). A Lab-score ≥3 showed the following characteristics: sensitivity 85.1% (95% CI: 76.5–93.6%), specificity 87.3% (95% CI: 82.7–91.8%), positive predictive value 68.7% (95% CI: 58.7–78.7%), negative predictive value 94.1% (95% CI: 91.5–97.9%), positive and negative likelihood ratios: 6.68 and 0.17 respectively. Area under the receiver operating characteristic curve was best for the Lab-score (0.911, 95% CI: 0.871–0.950). Discussion No difference regarding antibiotic treatment rate was observed when using the Lab-score, due to lack of adherence to the related recommendations. However, if strictly followed, a significant 26.5% reduction of antibiotic prescriptions would have been encountered. Medical education needs to be reinforced in order to observe rather than treat low-risk well-appearing children with FWS. Trial Registration ClinicalTrials.gov NCT02179398
    Electronic ISSN: 1932-6203
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    A Common Control Group - Optimising the Experiment Design to Maximise Sensitivity (2014)
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    In: PLoS ONE
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    Publication Date: 2014-12-12
    Description: by Simon Bate, Natasha A. Karp Methods for choosing an appropriate sample size in animal experiments have received much attention in the statistical and biological literature. Due to ethical constraints the number of animals used is always reduced where possible. However, as the number of animals decreases so the risk of obtaining inconclusive results increases. By using a more efficient experimental design we can, for a given number of animals, reduce this risk. In this paper two popular cases are considered, where planned comparisons are made to compare treatments back to control and when researchers plan to make all pairwise comparisons. By using theoretical and empirical techniques we show that for studies where all pairwise comparisons are made the traditional balanced design, as suggested in the literature, maximises sensitivity. For studies that involve planned comparisons of the treatment groups back to the control group, which are inherently more sensitive due to the reduced multiple testing burden, the sensitivity is maximised by increasing the number of animals in the control group while decreasing the number in the treated groups.
    Electronic ISSN: 1932-6203
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    Body Mass Index and Depressive Symptoms in Older Adults: A Cross-Lagged Panel Analysis (2014)
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    In: PLoS ONE
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    Publication Date: 2014-12-12
    Description: by Jinseok Kim, Jin-Won Noh, Jumin Park, Young Dae Kwon Background There are conflicting results about the association between body mass index (BMI) and depressive symptoms in older adults. The present study examined the relationship between weight and depressive symptoms over time in older adults in South Korea. Methods We used data from three waves of the Korean Longitudinal Study of Aging and ran a series of cross-lagged panel models to test the reciprocal relationship between depressive symptoms and obesity in older Korean adults. We assumed a temporally stable relationship between depressive symptoms and obesity and, thus imposed equality constraints over time. Results After controlling for the effect of depressive symptoms two years prior, underweight older adults had a higher depressive symptom score than those of normal weight. When controlling for obesity status from two years prior, older adults with higher levels of depressive symptoms were more likely to be underweight and less likely to be overweight than normal weight. The same patterns were observed in data from 2006 to 2008 and from 2008 to 2010. Conclusions These results show that there is a correlation between depressive symptoms and weight status. In middle-aged and elderly Asian populations, depression can lead to weight loss rather than obesity, and underweight may develop depressive symptoms.
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    The H I-dominated low-surface-brightness galaxy KKR 17 (2014)
    Oxford University Press
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    Publication Date: 2014-12-13
    Description: We present new narrow-band (Hα and [O  iii ]) images and optical spectrophotometry of H  ii regions for a gas-rich low-surface-brightness irregular galaxy, KKR 17. The central surface brightness of the galaxy is μ 0 ( B ) = 24.15 ± 0.03 mag s –2 . The galaxy was detected by the Arecibo Legacy Fast ALFA survey (ALFALFA). Its mass is dominated by neutral hydrogen (H  i ) gas. In contrast, both the stellar masses of the bright H  ii and diffuse stellar regions are small. In addition, the fit to the spectral energy distribution to each region shows the stellar populations of H  ii and diffuse regions are different. The bright H  ii region contains a large fraction of O-type stars, revealing recent strong star formation, whereas the diffuse region is dominated by median age stars with a typical age of ~600 Myr. Using McGaugh's abundance model, we found that the average metallicity of KKR 17 is 12 + (O/H) = 8.0 ± 0.1. The star-formation rate of KKR 17 is 0.21 ± 0.04 M  yr –1 , which is ~1/5 of our Milky Way's. Based on the analysis results for young stellar clusters in the H  ii region, the bright H  ii region has two sub-components with different velocities and metallicities. This may be caused by the outflow of massive stars or merging events. However, the mechanism triggering star formation in the H  ii region is still uncertain.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
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    A multiwavelength study of the M dwarf binary YY Geminorum (2014)
    Oxford University Press
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    Publication Date: 2014-12-13
    Description: We review the results of the 1988 multiwavelength campaign on the late-type eclipsing binary YY Geminorum. Observations include: broad-band optical and near-infrared photometry, simultaneous optical and ultraviolet ( IUE ) spectroscopy, X-ray ( Ginga ) and radio (VLA) data. From models fitted to the optical light curves, fundamental physical parameters have been determined together with evidence for transient maculations (spots) located near quadrature longitudes and intermediate latitudes. Eclipses were observed at optical, ultraviolet and radio wavelengths. Significant drops in 6 cm radio emission near the phases of both primary and secondary eclipse indicate relatively compact radio emitting volumes that may lie between the binary components. IUE observations during secondary eclipse are indicative of a uniform chromosphere saturated with Mg  ii emission and an extended volume of Lyα emission. Profile fitting of high-dispersion Hα spectra confirms the chromospheric saturation and indicates significant Hα opacity to heights of a few per cent of the photospheric radius. There is evidence for an enhanced Hα emission region visible near phase 0.25–0.35 which may be associated with a large spot on the primary and with two small optical flares which were also observed at other wavelengths: one in microwave radiation and the other in X-rays. For both flares, L X / L opt is consistent with energy release in closed magnetic structures.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
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  • 22
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    Eaten Out of House and Home: Impacts of Grazing on Ground-Dwelling Reptiles in Australian Grasslands and Grassy Woodlands (2014)
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    Publication Date: 2014-12-12
    Description: by Brett Howland, Dejan Stojanovic, Iain J. Gordon, Adrian D. Manning, Don Fletcher, David B. Lindenmayer Large mammalian grazers can alter the biotic and abiotic features of their environment through their impacts on vegetation. Grazing at moderate intensity has been recommended for biodiversity conservation. Few studies, however, have empirically tested the benefits of moderate grazing intensity in systems dominated by native grazers. Here we investigated the relationship between (1) density of native eastern grey kangaroos, Macropus giganteus , and grass structure, and (2) grass structure and reptiles (i.e. abundance, richness, diversity and occurrence) across 18 grassland and grassy Eucalyptus woodland properties in south-eastern Australia. There was a strong negative relationship between kangaroo density and grass structure after controlling for tree canopy cover. We therefore used grass structure as a surrogate for grazing intensity. Changes in grazing intensity (i.e. grass structure) significantly affected reptile abundance, reptile species richness, reptile species diversity, and the occurrence of several ground-dwelling reptiles. Reptile abundance, species richness and diversity were highest where grazing intensity was low. Importantly, no species of reptile was more likely to occur at high grazing intensities. Legless lizards ( Delma impar , D. inornata ) were more likely to be detected in areas subject to moderate grazing intensity, whereas one species ( Hemiergis talbingoensis ) was less likely to be detected in areas subject to intense grazing and three species ( Menetia greyii , Morethia boulengeri , and Lampropholis delicata ) did not appear to be affected by grazing intensity. Our data indicate that to maximize reptile abundance, species richness, species diversity, and occurrence of several individual species of reptile, managers will need to subject different areas of the landscape to moderate and low grazing intensities and limit the occurrence and extent of high grazing.
    Electronic ISSN: 1932-6203
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    Autonomous Inhibition of Apoptosis Correlates with Responsiveness of Colon Carcinoma Cell Lines to Ciglitazone (2014)
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    Publication Date: 2014-12-12
    Description: by David M. Baron, Ulrike Kaindl, Verena J. Haudek-Prinz, Editha Bayer, Clemens Röhrl, Christopher Gerner, Brigitte Marian Colorectal cancer is a leading cause of mortality worldwide. Resistance to therapy is common and often results in patients succumbing to the disease. The mechanisms of resistance are poorly understood. Cells basically have two possibilities to survive a treatment with potentially apoptosis-inducing substances. They can make use of their existing proteins to counteract the induced reactions or quickly upregulate protective factors to evade the apoptotic signal. To identify protein patterns involved in resistance to apoptosis, we studied two colorectal adenocarcinoma cell lines with different growth responses to low-molar concentrations of the thiazolidinedione Ciglitazone: HT29 cells underwent apoptosis, whereas SW480 cells increased cell number. Fluorescence detection and autoradiography scans of 2D-PAGE gels were performed in both cell lines to assess protein synthesis and turnover, respectively. To verify the data we performed shotgun analysis using the same treatment procedure as in 2D-experiments. Biological functions of the identified proteins were mainly associated with apoptosis regulation, chaperoning, intrinsic inflammation, and DNA repair. The present study suggests that different growth response of two colorectal carcinoma cell lines after treatment with Ciglitazone results from cell-specific protein synthesis and differences in protein regulation.
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    Correction: Molecular Determinants of Agonist Selectivity in Glutamate-Gated Chloride Channels Which Likely Explain the Agonist Selectivity of the Vertebrate Glycine and GABAA-ρ Receptors (2014)
    Public Library of Science (PLoS)
    In: PLoS ONE
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    Publication Date: 2014-12-12
    Description: by The PLOS ONE Staff
    Electronic ISSN: 1932-6203
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  • 25
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    Circadian Mechanisms of Food Anticipatory Rhythms in Rats Fed Once or Twice Daily: Clock Gene and Endocrine Correlates (2014)
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    Publication Date: 2014-12-12
    Description: by Danica F. Patton, Ângela M. Katsuyama, Ilya Pavlovski, Mateusz Michalik, Zachary Patterson, Maksim Parfyonov, Andrea N. Smit, Elliott G. Marchant, John Chung, Alfonso Abizaid, Kai-Florian Storch, Horacio de la Iglesia, Ralph E. Mistlberger Circadian clocks in many brain regions and peripheral tissues are entrained by the daily rhythm of food intake. Clocks in one or more of these locations generate a daily rhythm of locomotor activity that anticipates a regular mealtime. Rats and mice can also anticipate two daily meals. Whether this involves 1 or 2 circadian clocks is unknown. To gain insight into how the circadian system adjusts to 2 daily mealtimes, male rats in a 12∶12 light-dark cycle were fed a 2 h meal either 4 h after lights-on or 4 h after lights-off, or a 1 h meal at both times. After 30 days, brain, blood, adrenal and stomach tissue were collected at 6 time points. Multiple clock genes from adrenals and stomachs were assayed by RT-PCR. Blood was assayed for corticosterone and ghrelin. Bmal1 expression was quantified in 14 brain regions by in situ hybridization. Clock gene rhythms in adrenal and stomach from day-fed rats oscillated in antiphase with the rhythms in night-fed rats, and at an intermediate phase in rats fed twice daily. Corticosterone and ghrelin in 1-meal rats peaked at or prior to the expected mealtime. In 2-meal rats, corticosterone peaked only prior the nighttime meal, while ghrelin peaked prior to the daytime meal and then remained elevated. The olfactory bulb, nucleus accumbens, dorsal striatum, cerebellum and arcuate nucleus exhibited significant daily rhythms of Bmal1 in the night-fed groups that were approximately in antiphase in the day-fed groups, and at intermediate levels (arrhythmic) in rats anticipating 2 daily meals. The dissociations between anticipatory activity and the peripheral clocks and hormones in rats anticipating 2 daily meals argue against a role for these signals in the timing of behavioral rhythms. The absence of rhythmicity at the tissue level in brain regions from rats anticipating 2 daily meals support behavioral evidence that circadian clock cells in these tissues may reorganize into two populations coupled to different meals.
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    Use of a Guinea Pig-Specific Transcriptome Array for Evaluation of Protective Immunity against Genital Chlamydial Infection following Intranasal Vaccination in Guinea Pigs (2014)
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    Publication Date: 2014-12-12
    Description: by Shradha Wali, Rishein Gupta, Ronald L. Veselenak, Yansong Li, Jieh-Juen Yu, Ashlesh K. Murthy, Andrew P. Cap, M. Neal Guentzel, James P. Chambers, Guangming Zhong, Roger G. Rank, Richard B. Pyles, Bernard P. Arulanandam Guinea pigs have been used as a second animal model to validate putative anti-chlamydial vaccine candidates tested in mice. However, the lack of guinea pig-specific reagents has limited the utility of this animal model in Chlamydia sp . vaccine studies. Using a novel guinea pig-specific transcriptome array, we determined correlates of protection in guinea pigs vaccinated with Chlamydia caviae ( C. caviae ) via the intranasal route, previously reported by us and others to provide robust antigen specific immunity against subsequent intravaginal challenge. C. caviae vaccinated guinea pigs resolved genital infection by day 3 post challenge. In contrast, mock vaccinated animals continued to shed viable Chlamydia up to day 18 post challenge. Importantly, at day 80 post challenge, vaccinated guinea pigs experienced significantly reduced genital pathology - a sequelae of genital chlamydial infections, in comparison to mock vaccinated guinea pigs. Sera from vaccinated guinea pigs displayed antigen specific IgG responses and increased IgG1 and IgG2 titers capable of neutralizing GPIC in vitro . Th1-cellular/inflammatory immune genes and Th2-humoral associated genes were also found to be elevated in vaccinated guinea pigs at day 3 post-challenge and correlated with early clearance of the bacterium. Overall, this study provides the first evidence of guinea pig-specific genes involved in anti-chlamydial vaccination and illustrates the enhancement of the utility of this animal model in chlamydial pathogenesis.
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    Correction: Genome-Wide Associations between Genetic and Epigenetic Variation Influence mRNA Expression and Insulin Secretion in Human Pancreatic Islets (2014)
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    Publication Date: 2014-12-13
    Description: by The PLOS Genetics Staff
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
    Topics: Biology
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    Evolutionary Phylodynamics of Korean Noroviruses Reveals a Novel GII.2/GII.10 Recombination Event (2014)
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    Publication Date: 2014-12-13
    Description: by Thoi Cong Truong, Van Thai Than, Wonyong Kim Viral gastroenteritis is the most common causal agent of public health problems worldwide. Noroviruses cause nonbacterial acute gastroenteritis in humans of all ages. In this study, we investigated the occurrence of norovirus infection in children with acute gastroenteritis admitted to university hospitals in South Korea. We also analyzed the genetic diversity of the viruses and identified novel recombination events among the identified viral strains. Of 502 children with acute gastroenteritis admitted to our three hospitals between January 2011 and March 2012, genotyping of human noroviruses was performed in 171 (34%) norovirus-positive samples. Of these samples, 170 (99.5%) were in genogroup II (GII), while only one (0.5%) was in genogroup I (GI). The most common GII strain was the GII.4-2006b variant (n = 96, 56.5%), followed by GII.6 (n = 23, 13.5%), GII.12 (n = 22, 12.9%), GII.3 (n = 20, 11.8%), GII.2 (n = 6, 3.5%), GII.b (n = 2, 1.2%), and GII.10 (n = 1, 0.6%). Potential recombination events (polymerase/capsid) were detected in 39 GII strains (22.9%), and the most frequent genotypes were GII.4/GII.12 (n = 12, 30.8%), GII.4/GII.6 (n = 12, 30.8%), GII.4/GII.3 (n = 8, 20.5%), GII.b/GII.3 (n = 3, 7.7%), GII.16/GII.2 (n = 2, 5.1%), GII.4/GII.2 (n = 1, 2.6%), and GII.2/GII.10 (n = 1, 2.6%). For the first time, a novel GII.2/GII.10 recombination was detected; we also identified the GII.16/GII.2 strain for the first time in South Korea. Our data provided important insights into new recombination events, which may prove valuable for predicting the emergence of circulating norovirus strains with global epidemic potential.
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    Paramagnetic Beads and Magnetically Mediated Strain Enhance Cardiomyogenesis in Mouse Embryoid Bodies (2014)
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    Publication Date: 2014-12-13
    Description: by Laura R. Geuss, Douglas C. Wu, Divya Ramamoorthy, Corinne D. Alford, Laura J. Suggs Mechanical forces play an important role in proper embryologic development, and similarly such forces can directly impact pluripotency and differentiation of mouse embryonic stem cells (mESC) in vitro . In addition, manipulation of the embryoid body (EB) microenvironment, such as by incorporation of microspheres or microparticles, can similarly influence fate determination. In this study, we developed a mechanical stimulation regimen using permanent neodymium magnets to magnetically attract cells within an EB. Arginine-Glycine-Aspartic Acid (RGD)-conjugated paramagnetic beads were incorporated into the interior of the EBs during aggregation, allowing us to exert force on individual cells using short-term magnetization. EBs were stimulated for one hour at different magnetic field strengths, subsequently exerting a range of force intensity on the cells at different stages of early EB development. Our results demonstrated that following exposure to a 0.2 Tesla magnetic field, ESCs respond to magnetically mediated strain by activating Protein Kinase A (PKA) and increasing phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) expression. The timing of stimulation can also be tailored to guide ESC differentiation: the combination of bone morphogenetic protein 4 (BMP4) supplementation with one hour of magnetic attraction on Day 3 enhances cardiomyogenesis by increasing contractile activity and the percentage of sarcomeric α-actin-expressing cells compared to control samples with BMP4 alone. Interestingly, we also observed that the beads alone had some impact on differentiation by increasingly slightly, albeit not significantly, the percentage of cardiomyocytes. Together these results suggest that magnetically mediated strain can be used to enhance the percentage of mouse ESC-derived cardiomyocytes over current differentiation protocols.
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    Efficacy and Safety of Crizotinib among Chinese EML4-ALK-Positive, Advanced-Stage Non-Small Cell Lung Cancer Patients (2014)
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    In: PLoS ONE
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    Publication Date: 2014-12-13
    Description: by Yabing Cao, Guangli Xiao, Xibin Qiu, Sheng Ye, Tongyu Lin Introduction We report the efficacy and safety of crizotinib treatment among Chinese patients with advanced-stage NSCLC. Methods We retrospectively analyzed patients with EML4-ALK positive advanced NSCLC who were treated with crizotinib from May 2012 to Aug 2013. Baseline clinical parameters, treatment protocol, response to therapy and survival were noted. The primary goal was to evaluate the efficacy of crizotinib in patients who were previously treated patients or who had poor ECOG performance status (PS). Results Forty patients were evaluable for safety and efficacy. Median age was 43 years, 100% had adenocarcinoma and stage IV disease, and 42.5% were female. Six patients received frontline treatment with crizotinib, 17 patients had 1 prior treatment, and 17 patients had more than 2 lines of prior treatment. Patients received a median of 5 cycles of treatment (range 1–15 cycles). After the first cycle, 92.5% (37/40) patients archived partial remission (PR). At the end of the follow-up period, the overall PR rate was 70% (28/40), and progression of disease (PD) occurred in 30% of patients (12/40). The median PFS was 28 weeks (95% CI 15.4 to 40.5 weeks), and median OS was 40 weeks (95% CI 38.6 to 49.3 weeks). The most frequent treatment-related AEs were vomiting (47.5%), vision disorder (27.5%) and increased ALT/AST (42%); most toxicities were Grade 1/2. Observed treatment-related Grade 3/4 AEs included increased ALT/AST (10%) and vomiting (5%). The EML4-ALK fusion rate and number of prior chemotherapy cycles did not appear to significantly affect the efficacy of crizotinib. However, PS 0–2 patients had improved PFS (50 weeks vs. 24 weeks, p = 0.015). Conclusions Crizotinib was safe, well-tolerated, and effective in Chinese patients with pre-treated ALK-rearranged NSCLC. QOL was improved and PS appears to have an effect on the efficacy of crizotinib, but prior treatment and ALK fusion rate do not.
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    Detection of DNA Sequences Refractory to PCR Amplification Using a Biophysical SERRS Assay (Surface Enhanced Resonant Raman Spectroscopy) (2014)
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    Publication Date: 2014-12-13
    Description: by Cécile Feuillie, Maxime M. Merheb, Benjamin Gillet, Gilles Montagnac, Isabelle Daniel, Catherine Hänni The analysis of ancient or processed DNA samples is often a great challenge, because traditional Polymerase Chain Reaction – based amplification is impeded by DNA damage. Blocking lesions such as abasic sites are known to block the bypass of DNA polymerases, thus stopping primer elongation. In the present work, we applied the SERRS-hybridization assay, a fully non-enzymatic method, to the detection of DNA refractory to PCR amplification. This method combines specific hybridization with detection by Surface Enhanced Resonant Raman Scattering (SERRS). It allows the detection of a series of double-stranded DNA molecules containing a varying number of abasic sites on both strands, when PCR failed to detect the most degraded sequences. Our SERRS approach can quickly detect DNA molecules without any need for DNA repair. This assay could be applied as a pre-requisite analysis prior to enzymatic reparation or amplification. A whole new set of samples, both forensic and archaeological, could then deliver information that was not yet available due to a high degree of DNA damage.
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    Accumulation of Oxidized LDL in the Tendon Tissues of C57BL/6 or Apolipoprotein E Knock-Out Mice That Consume a High Fat Diet: Potential Impact on Tendon Health (2014)
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    In: PLoS ONE
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    Publication Date: 2014-12-13
    Description: by Navdeep Grewal, Gail M. Thornton, Hayedeh Behzad, Aishwariya Sharma, Alex Lu, Peng Zhang, W. Darlene Reid, David J. Granville, Alex Scott Objective Clinical studies have suggested an association between dyslipidemia and tendon injuries or chronic tendon pain; the mechanisms underlying this association are not yet known. The objectives of this study were (1) to evaluate the impact of a high fat diet on the function of load-bearing tendons and on the distribution in tendons of oxidized low density lipoprotein (oxLDL), and (2) to examine the effect of oxLDL on tendon fibroblast proliferation and gene expression. Methods Gene expression ( Mmp2, Tgfb1 , Col1a1 , Col3a1 ), fat content (Oil Red O staining), oxLDL levels (immunohistochemistry) and tendon biomechanical properties were examined in mice (C57Bl/6 or ApoE -/-) receiving a standard or a high fat diet. Human tendon fibroblast proliferation and gene expression ( COL1A1 , COL3A1 , MMP2 ) were examined following oxLDL exposure. Results In both types of mice (C57Bl/6 or ApoE -/-), consumption of a high fat diet led to a marked increase in oxLDL deposition in the load-bearing extracellular matrix of the tendon. The consumption of a high fat diet also reduced the failure stress and load of the patellar tendon in both mouse types, and increased Mmp2 expression. ApoE -/- mice exhibited more pronounced reductions in tendon function than wild-type mice, and decreased expression of Col1a1 compared to wild type mice. Human tendon fibroblasts responded to oxLDL by increasing their proliferation and their mRNA levels of MMP2 , while decreasing their mRNA levels for COL1A1 and COL3A1 . Conclusion The consumption of a high fat diet resulted in deleterious changes in tendon function, and these changes may be explained in part by the effects of oxLDL, which induced a proliferative, matrix-degrading phenotype in human tenocytes.
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    Neuroprotective and Anti-Inflammatory Roles of the Phosphatase and Tensin Homolog Deleted on Chromosome Ten (PTEN) Inhibition in a Mouse Model of Temporal Lobe Epilepsy (2014)
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    Publication Date: 2014-12-13
    Description: by Valentina Grande, Giusi Manassero, Alessandro Vercelli Excitotoxic damage represents the major mechanism leading to cell death in many human neurodegenerative diseases such as ischemia, trauma and epilepsy. Caused by an excess of glutamate that acts on metabotropic and ionotropic excitatory receptors, excitotoxicity activates several death signaling pathways leading to an extensive neuronal loss and a consequent strong activation of astrogliosis. Currently, the search for a neuroprotective strategy is aimed to identify the level in the signaling pathways to block excitotoxicity avoiding the loss of important physiological functions and side effects. To this aim, PTEN can be considered an ideal candidate: downstream the excitatory receptors activated in excitotoxicity (whose inhibition was shown to be not clinically viable), it is involved in neuronal damage and in the first stage of the reactive astrogliosis in vivo . In this study, we demonstrated the involvement of PTEN in excitotoxicity through its pharmacological inhibition by dipotassium bisperoxo (picolinato) oxovanadate [bpv(pic)] in a model of temporal lobe epilepsy, obtained by intraperitoneal injection of kainate in 2-month-old C57BL/6J male mice. We have demonstrated that inhibition of PTEN by bpv(pic) rescues neuronal death and decreases the reactive astrogliosis in the CA3 area of the hippocampus caused by systemic administration of kainate. Moreover, the neurotoxin administration increases significantly the scanty presence of mitochondrial PTEN that is significantly decreased by the administration of the inhibitor 6 hr after the injection of kainate, suggesting a role of PTEN in mitochondrial apoptosis. Taken together, our results confirm the key role played by PTEN in the excitotoxic damage and the strong anti-inflammatory and neuroprotective potential of its inhibition.
    Electronic ISSN: 1932-6203
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    Phlebotomy Treatment for Elimination of Perfluoroalkyl Acids in a Highly Exposed Family: A Retrospective Case-Series (2014)
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    Publication Date: 2014-12-13
    Description: by Stephen J. Genuis, Yanna Liu, Quentin I. T. Genuis, Jonathan W. Martin Background Perfluoroalkyl acids (PFAAs) are a family of commonly used synthetic chemicals that have become widespread environmental contaminants. In human serum, perfluorohexane sulfonate (PFHxS), perflurooctane sulfonate (PFOS), and perfluorooctanoate (PFOA) are most frequently detected, in part owing to their long elimination half-lives of between 3.8 yrs (PFOA) and 8.5 yrs (PFHxS). These PFAAs also cross the placenta and have been associated with developmental toxicity, and some are considered likely human carcinogens. Interventions to eliminate PFAAs in highly contaminated individuals would reduce future health risks, but minimal research has been conducted on methods to facilitate accelerated human clearance of these persistent substances. Methods Six patients with elevated serum concentrations from a single family were treated by intermittent phlebotomy over a 4–5 year period at intervals similar to, or less frequent than what is done for routine blood donation at Canadian Blood Services. The apparent elimination half-life (HL app ) for PFHxS, PFOS, and PFOA in this treated population was calculated in each patient and compared to the intrinsic elimination half-lives (HL in ) from a literature reference population of untreated fluorochemical manufacturing plant retirees (n = 26, age 〉55 yrs). Results For all three PFAAs monitored during phlebotomy, HL app in each of the family members (except the mother, who had a low rate of venesection) was significantly shorter than the geometric mean HL measured in the reference population, and in some cases were even shorter compared to the fastest eliminator in the reference population. Conclusion This study suggests significantly accelerated PFAA clearance with regular phlebotomy treatment, but the small sample size and the lack of controls in this clinical intervention precludes drawing firm conclusions. Given the minimal risks of intermittent phlebotomy, this may be an effective and safe clinical intervention to diminish the body burden of PFAAs in highly exposed people.
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    The Duration of Hypotension Determines the Evolution of Bacteremia-Induced Acute Kidney Injury in the Intensive Care Unit (2014)
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    Publication Date: 2014-12-13
    Description: by Karin Janssen van Doorn, Walter Verbrugghe, Kristien Wouters, Hilde Jansens, Philippe G. Jorens Background Exploration of the impact of severe hypotension on the evolution of acute kidney injury in septic patients. Methods and Results We reviewed the hemodynamic parameters of 137 adults with septic shock and proven blood stream infection in the ICU. Severe hypotension was defined as a mean arterial blood pressure (MAP) ≤65 mmHg. The influence of the duration of severe hypotension on the evolution of acute kidney injury was evaluated according to the RIFLE classification, with day 0 defined as the day of a positive blood stream infection. After bloodstream infection, the probability for a patient to be in Failure was significantly higher than before blood stream infection (OR = 1.94, p = 0.0276). Patients have a significantly higher risk of evolving to Failure if the duration of severe hypotension is longer (OR = 1.02 for each 10 minutes increase in duration of a MAP
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    An efficient radiative cooling approximation for use in hydrodynamic simulations (2014)
    Oxford University Press
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    Publication Date: 2014-12-14
    Description: To make relevant predictions about observable emission, hydrodynamical simulation codes must employ schemes that account for radiative losses, but the large dimensionality of accurate radiative transfer schemes is often prohibitive. Stamatellos and collaborators introduced a scheme for smoothed particle hydrodynamics (SPH) simulations based on the notion of polytropic pseudo-clouds that uses only local quantities to estimate cooling rates. The computational approach is extremely efficient and works well in cases close to spherical symmetry, such as in star formation problems. Unfortunately, the method, which takes the local gravitational potential as an input, can be inaccurate when applied to non-spherical configurations, limiting its usefulness when studying discs or stellar collisions, among other situations of interest. Here, we introduce the ‘pressure scale height method,’ which incorporates the fluid pressure scaleheight into the determination of column densities and cooling rates, and show that it produces more accurate results across a wide range of physical scenarios while retaining the computational efficiency of the original method. The tested models include spherical polytropes as well as discs with specified density and temperature profiles. We focus on applying our techniques within an SPH code, although our method can be implemented within any particle-based Lagrangian or grid-based Eulerian hydrodynamic scheme. Our new method may be applied in a broad range of situations, including within the realm of stellar interactions, collisions, and mergers.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
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    Correction: Population Genetics of the São Tomé Caecilian (Gymnophiona: Dermophiidae: Schistometopum thomense) Reveals Strong Geographic Structuring (2014)
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    Publication Date: 2014-12-16
    Description: by The PLOS ONE Staff
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    Correction: Mycobacterium tuberculosis Requires the ECF Sigma Factor SigE to Arrest Phagosome Maturation (2014)
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    Publication Date: 2014-12-16
    Description: by The PLOS ONE Staff
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    Correction: Molecular Phylogenetics and Systematics of the Bivalve Family Ostreidae Based on rRNA Sequence-Structure Models and Multilocus Species Tree (2014)
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    Publication Date: 2014-12-16
    Description: by The PLOS ONE Staff
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    Identification of Neonatal White Matter on DTI: Influence of More Inclusive Thresholds for Atlas Segmentation (2014)
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    Publication Date: 2014-12-16
    Description: by Rachel L. Vassar, Naama Barnea-Goraly, Jessica Rose Purpose Semi-automated diffusion tensor imaging (DTI) analysis of white matter (WM) microstructure offers a clinically feasible technique to assess neonatal brain development and provide early prognosis, but is limited by variable methods and insufficient evidence regarding optimal parameters. The purpose of this research was to investigate the influence of threshold values on semi-automated, atlas-based brain segmentation in very-low-birth-weight (VLBW) preterm infants at near-term age. Materials and Methods DTI scans were analyzed from 45 VLBW preterm neonates at near-term-age with no brain abnormalities evident on MRI. Brain regions were selected with a neonatal brain atlas and threshold values: trace 0.15, FA〉0.20, and FA〉0.25. Relative regional volumes, FA, axial diffusivity (AD), and radial diffusivity (RD) were compared for twelve WM regions. Results Near-term brain regions demonstrated differential effects from segmentation with the three FA thresholds. Regional DTI values and volumes selected in the PLIC, CereP, and RLC varied the least with the application of different FA thresholds. Overall, application of higher FA thresholds significantly reduced brain region volume selected, increased variability, and resulted in higher FA and lower RD values. The lower threshold FA〉0.15 selected 78±21% of original volumes segmented by the atlas, compared to 38±12% using threshold FA〉0.25. Conclusion Results indicate substantial and differential effects of atlas-based DTI threshold parameters on regional volume and diffusion scalars. A lower, more inclusive FA threshold than typically applied for adults is suggested for consistent analysis of WM regions in neonates.
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    Urinary Excretion of Fatty Acid-Binding Protein 4 is Associated with Albuminuria and Renal Dysfunction (2014)
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    Publication Date: 2014-12-16
    Description: by Yusuke Okazaki, Masato Furuhashi, Marenao Tanaka, Tomohiro Mita, Takahiro Fuseya, Shutaro Ishimura, Yuki Watanabe, Kyoko Hoshina, Hiroshi Akasaka, Hirofumi Ohnishi, Hideaki Yoshida, Shigeyuki Saitoh, Kazuaki Shimamoto, Tetsuji Miura Background Fatty acid-binding protein 4 (FABP4/A-FABP/aP2) is expressed in not only adipocytes and macrophages but also peritubular capillaries in the normal kidney. We recently demonstrated that ectopic expression of FABP4, but not FABP1 known as liver FABP (L-FABP), in the glomerulus is associated with progression of proteinuria and renal dysfunction. However, urinary excretion of FABP4 has not been investigated. Methods Subjects who participated in the Tanno-Sobetsu Study, a study with a population-based cohort design, in 2011 (n = 392, male/female: 166/226) were enrolled. Urinary FABP4 (U-FABP4) and urinary albumin-to-creatinine ratio (UACR) were measured. Change in estimated glomerular filtration rate (eGFR) was followed up one year later. Results In 93 (23.7%) of the 392 subjects, U-FABP4 level was below the sensitivity of the assay. Subjects with undetectable U-FABP4 were younger and had lower UACR and higher eGFR levels than subjects with measurable U-FABP4. U-FABP4 level was positively correlated with age, systolic blood pressure and levels of serum FABP4 (S-FABP4), triglycerides, hemoglobin A1c (HbA1c), urinary FABP1 (U-FABP1) and UACR (r = 0.360, p
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    Age-Related Longitudinal Changes in Metabolic Energy Expenditure during Walking in Boys with Duchenne Muscular Dystrophy (2014)
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    Publication Date: 2014-12-16
    Description: by Merel-Anne Brehm, Jiska C. E. Kempen, Anneke J. van der Kooi, Imelda J. M. de Groot, Janneke C. van den Bergen, Jan J. G. M. Verschuuren, Erik H. Niks, Jaap Harlaar Objective The aim of this study was to evaluate age-related changes in metabolic walking energy expenditure in ambulant boys affected by Duchenne muscular dystrophy over a follow-up period of 12 months. Methods At baseline (T1) and 12 months later (T2), metabolic walking energy expenditure was assessed during a 6-minute walk test at comfortable speed in 14 ambulant boys with Duchenne (age range: 6.0-12.5 years, mean 8.2). Outcome measures derived from the assessment included the 6-minute comfortable walking distance (m) and net-nondimensional energy cost relative to speed-matched control cost (SMC-EC, %). Statistical comparisons were made using a two-way repeated measures ANOVA (factors: time (T1 versus T2) and age ( 0.158), and also there were no interaction effects (p〉0.248). Conclusions The results of our small study suggest that the natural course of walking performance in ambulant boys with Duchenne is characterized by a decrease in comfortable walking distance and an increase in walking energy cost. The rate of energy cost seems to increase with age, while walking distance decreases, which is opposite from the trend in typically developing children.
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  • 43
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    Hepatic Farnesoid X-Receptor Isoforms α2 and α4 Differentially Modulate Bile Salt and Lipoprotein Metabolism in Mice (2014)
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    Publication Date: 2014-12-16
    Description: by Marije Boesjes, Vincent W. Bloks, Jurre Hageman, Trijnie Bos, Theo H. van Dijk, Rick Havinga, Henk Wolters, Johan W. Jonker, Folkert Kuipers, Albert K. Groen The nuclear receptor FXR acts as an intracellular bile salt sensor that regulates synthesis and transport of bile salts within their enterohepatic circulation. In addition, FXR is involved in control of a variety of crucial metabolic pathways. Four FXR splice variants are known, i.e. FXRα1-4. Although these isoforms show differences in spatial and temporal expression patterns as well as in transcriptional activity, the physiological relevance hereof has remained elusive. We have evaluated specific roles of hepatic FXRα2 and FXRα4 by stably expressing these isoforms using liver-specific self-complementary adeno-associated viral vectors in total body FXR knock-out mice. The hepatic gene expression profile of the FXR knock-out mice was largely normalized by both isoforms. Yet, differential effects were also apparent; FXRα2 was more effective in reducing elevated HDL levels and transrepressed hepatic expression of Cyp8b1, the regulator of cholate synthesis. The latter coincided with a switch in hydrophobicity of the bile salt pool. Furthermore, FXRα2-transduction caused an increased neutral sterol excretion compared to FXRα4 without affecting intestinal cholesterol absorption. Our data show, for the first time, that hepatic FXRα2 and FXRα4 differentially modulate bile salt and lipoprotein metabolism in mice.
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    Mitochondrial COI and 16sRNA Evidence for a Single Species Hypothesis of E. vitis, J. formosana and E. onukii in East Asia (2014)
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    Publication Date: 2014-12-16
    Description: by Jian-Yu Fu, Bao-Yu Han, Qiang Xiao Tea green leafhopper is one of the most damaging tea pests in main tea production regions of East Asia. For lack of recognized morphological characters, the dominant species of tea green leafhoppers in Mainland China, Taiwan and Japan have always been named as Empoasca vitis Göthe, Jacobiasca formosana Paoli and Empoasca onukii MATSUDA, respectively. Furthermore, nothing is known about the genetic relationships among them. In this study, we collected six populations from Mainland China, four populations from Japan and one population from Taiwan, and examined the genetic distances in the COI and 16sRNA regions of mtDNA among them. The results showed that the genetic distances based on single gene or the combined sequences among eleven leafhopper populations were 0.3–1.2%, which were all less than the species boundary of 2%. Moreover, there were at least two haplotypes shared by two distinct populations from different regions. The phylogenetic analysis based on single gene or combined sets also supported that tea green leafhoppers from Mainland China, Taiwan and Japan were closely related to each other, and there were at least two specimens from different regions clustered ahead of those from the same region. Therefore, we propose that the view of recognizing the dominant species of tea green leafhoppers in three adjacent tea production regions of East Asia as different species is unreliable or questionable and suggest that they are a single species.
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    Correction: A Natural Plasmid Uniquely Encodes Two Biosynthetic Pathways Creating a Potent Anti-MRSA Antibiotic (2014)
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  • 46
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    Correction: Endogenous Retrovirus EAV-HP Linked to Blue Egg Phenotype in Mapuche Fowl (2014)
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  • 47
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    Metabolism of Skin-Absorbed Resveratrol into Its Glucuronized Form in Mouse Skin (2014)
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    Publication Date: 2014-12-16
    Description: by Itsuo Murakami, Romanas Chaleckis, Tomáš Pluskal, Ken Ito, Kousuke Hori, Masahiro Ebe, Mitsuhiro Yanagida, Hiroshi Kondoh Resveratrol (RESV) is a plant polyphenol, which is thought to have beneficial metabolic effects in laboratory animals as well as in humans. Following oral administration, RESV is immediately catabolized, resulting in low bioavailability. This study compared RESV metabolites and their tissue distribution after oral uptake and skin absorption. Metabolomic analysis of various mouse tissues revealed that RESV can be absorbed and metabolized through skin. We detected sulfated and glucuronidated RESV metabolites, as well as dihydroresveratrol. These metabolites are thought to have lower pharmacological activity than RESV. Similar quantities of most RESV metabolites were observed 4 h after oral or skin administration, except that glucuronidated RESV metabolites were more abundant in skin after topical RESV application than after oral administration. This result is consistent with our finding of glucuronidated RESV metabolites in cultured skin cells. RESV applied to mouse ears significantly suppressed inflammation in the TPA inflammation model. The skin absorption route could be a complementary, potent way to achieve therapeutic effects with RESV.
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    Intranasal Administration of Recombinant TRAIL Down-Regulates CXCL-1/KC in an Ovalbumin-Induced Airway Inflammation Murine Model (2014)
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    Publication Date: 2014-12-16
    Description: by Veronica Tisato, Chiara Garrovo, Stefania Biffi, Francesca Petrera, Rebecca Voltan, Fabio Casciano, Germana Meroni, Chiara Agnoletto, Giorgio Zauli, Paola Secchiero Ovalbumin (OVA)-sensitized BALB/c mice were i.n. instilled with recombinant TNF-related apoptosis inducing ligand (TRAIL) 24 hours before OVA challenge. The total number of leukocytes and the levels of the chemokine CXCL-1/KC significantly increased in the bronchoalveolar lavage (BAL) fluids of allergic animals with respect to control littermates, but not in the BAL of mice i.n. pretreated with recombinant TRAIL before OVA challenge. In particular, TRAIL pretreatment significantly reduced the BAL percentage of both eosinophils and neutrophils. On the other hand, when TRAIL was administrated simultaneously to OVA challenge its effect on BAL infiltration was attenuated. Overall, the results show that the i.n. pretreatment with TRAIL down-modulated allergic airway inflammation.
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    Correction: Combined Treatment of Xenon and Hypothermia in Newborn Rats - Additive or Synergistic Effect? (2014)
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    Improved HIV Awareness and Perceived Empowerment to Negotiate Safe Sex among Married Women in Ethiopia between 2005 and 2011 (2014)
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    Publication Date: 2014-12-16
    Description: by Zaake De Coninck, Ibrahim A. Feyissa, Anna Mia Ekström, Gaetano Marrone Introduction The HIV prevalence rate in Ethiopia for married (or cohabiting) women is 3 times that found amongst women who have never been married. While marriage used to be seen as a protective factor against HIV, evidence suggests that this is no longer necessarily the case. This study analyses the trend and socio-demographic determinants of HIV awareness and safe sex negotiation among married women in Ethiopia between 2005 and 2011. Methods Data from Ethiopian Demographic and Health Surveys conducted in 2005 and in 2011 were analysed. Socio-demographic variables as well as ‘survey year’ were selected to assess their interaction with selected HIV awareness and safe sex negotiation indicators. Multivariable regression analyses were performed. Odds ratios and confidence intervals were computed. Results A significant increase in knowledge of HIV and ability to negotiate safer sex occurred between 2005 and 2011 reflecting a positive trend in gender empowerment amongst married Ethiopian women. Some of these advancements were striking, for instance respondents were 3.6 times more likely to have “Heard of AIDS” in 2011 than in 2005. HIV awareness and safer sex negotiation were significantly associated with higher education, higher socioeconomic status, those who had heard of HIV, those of the Orthodox Christian faith, and (to some extent) those living in rural areas. Conclusion HIV awareness has increased significantly in Ethiopia over the last decade but married women are still disproportionately susceptible to HIV. Community programmes, already effective in Ethiopia, also need to target this vulnerable sub-group of women.
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    Protoporphyrins Enhance Oligomerization and Enzymatic Activity of HtrA1 Serine Protease (2014)
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    Publication Date: 2014-12-16
    Description: by Hakryul Jo, Victoria Patterson, Sean Stoessel, Chia-Yi Kuan, Josephine Hoh High temperature requirement protein A1 (HtrA1), a secreted serine protease of the HtrA family, is associated with a multitude of human diseases. However, the exact functions of HtrA1 in these diseases remain poorly understood. We seek to unravel the mechanisms of HtrA1 by elucidating its interactions with chemical or biological modulators. To this end, we screened a small molecule library of 500 bioactive compounds to identify those that alter the formation of extracellular HtrA1 complexes in the cell culture medium. An initial characterization of two novel hits from this screen showed that protoporphyrin IX (PPP-IX), a precursor in the heme biosynthetic pathway, and its metalloporphyrin (MPP) derivatives fostered the oligomerization of HtrA1 by binding to the protease domain. As a result of the interaction with MPPs, the proteolytic activity of HtrA1 against Fibulin-5, a specific HtrA1 substrate in age-related macular degeneration (AMD), was increased. This physical interaction could be abolished by the missense mutations of HtrA1 found in patients with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). Furthermore, knockdown of HtrA1 attenuated apoptosis induced by PPP-IX. These results suggest that PPP-IX, or its derivatives, and HtrA1 may function as co-factors whereby porphyrins enhance oligomerization and the protease activity of HtrA1, while active HtrA1 elevates the pro-apoptotic actions of porphyrin derivatives. Further analysis of this interplay may shed insights into the pathogenesis of diseases such as AMD, CARASIL and protoporphyria, as well as effective therapeutic development.
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    Dissociable Neural Mechanisms Underlying the Modulation of Pain and Anxiety? An fMRI Pilot Study (2014)
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    Publication Date: 2014-12-16
    Description: by Katja Wiech, Robert Edwards, Graham Lorimer Moseley, Chantal Berna, Markus Ploner, Irene Tracey The down-regulation of pain through beliefs is commonly discussed as a form of emotion regulation. In line with this interpretation, the analgesic effect has been shown to co-occur with reduced anxiety and increased activity in the ventrolateral prefrontal cortex (VLPFC), which is a key region of emotion regulation. This link between pain and anxiety modulation raises the question whether the two effects are rooted in the same neural mechanism. In this pilot fMRI study, we compared the neural basis of the analgesic and anxiolytic effect of two types of threat modulation: a “behavioral control” paradigm, which involves the ability to terminate a noxious stimulus, and a “safety signaling” paradigm, which involves visual cues that signal the threat (or absence of threat) that a subsequent noxious stimulus might be of unusually high intensity. Analgesia was paralleled by VLPFC activity during behavioral control. Safety signaling engaged elements of the descending pain control system, including the rostral anterior cingulate cortex that showed increased functional connectivity with the periaqueductal gray and VLPFC. Anxiety reduction, in contrast, scaled with dorsolateral prefrontal cortex activation during behavioral control but had no distinct neural signature during safety signaling. Our pilot data therefore suggest that analgesic and anxiolytic effects are instantiated in distinguishable neural mechanisms and differ between distinct stress- and pain-modulatory approaches, supporting the recent notion of multiple pathways subserving top-down modulation of the pain experience. Additional studies in larger cohorts are needed to follow up on these preliminary findings.
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    Acoustic Telemetry Reveals Large-Scale Migration Patterns of Walleye in Lake Huron (2014)
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    Publication Date: 2014-12-16
    Description: by Todd A. Hayden, Christopher M. Holbrook, David G. Fielder, Christopher S. Vandergoot, Roger A. Bergstedt, John M. Dettmers, Charles C. Krueger, Steven J. Cooke Fish migration in large freshwater lacustrine systems such as the Laurentian Great Lakes is not well understood. The walleye ( Sander vitreus ) is an economically and ecologically important native fish species throughout the Great Lakes. In Lake Huron walleye has recently undergone a population expansion as a result of recovery of the primary stock, stemming from changing food web dynamics. During 2011 and 2012, we used acoustic telemetry to document the timing and spatial scale of walleye migration in Lake Huron and Saginaw Bay. Spawning walleye ( n  = 199) collected from a tributary of Saginaw Bay were implanted with acoustic tags and their migrations were documented using acoustic receivers ( n  = 140) deployed throughout U.S. nearshore waters of Lake Huron. Three migration pathways were described using multistate mark-recapture models. Models were evaluated using the Akaike Information Criterion. Fish sex did not influence migratory behavior but did affect migration rate and walleye were detected on all acoustic receiver lines. Most (95%) tagged fish migrated downstream from the riverine tagging and release location to Saginaw Bay, and 37% of these fish emigrated from Saginaw Bay into Lake Huron. Remarkably, 8% of walleye that emigrated from Saginaw Bay were detected at the acoustic receiver line located farthest from the release location more than 350 km away. Most (64%) walleye returned to the Saginaw River in 2012, presumably for spawning. Our findings reveal that fish from this stock use virtually the entirety of U.S. nearshore waters of Lake Huron.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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    Healthy Dietary Interventions and Lipoprotein (a) Plasma Levels: Results from the Omni Heart Trial (2014)
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    Publication Date: 2014-12-16
    Description: by Bernhard Haring, Moritz C. Wyler von Ballmoos, Lawrence J. Appel, Frank M. Sacks Background Increased lipoprotein(a) [Lp(a)] levels are associated with atherosclerotic cardiovascular disease. Studies of dietary interventions on changes in Lp(a) are sparse. We aimed to compare the effects of three healthy dietary interventions differing in macronutrient content on Lp(a) concentration. Methods Secondary analysis of a randomized, 3-period crossover feeding study including 155 (89 blacks; 66 whites) individuals. Participants were given DASH-type healthy diets rich in carbohydrates [Carb], in protein [Prot] or in unsaturated fat [Unsat Fat] for 6 weeks each. Plasma Lp(a) concentration was assessed at baseline and after each diet. Results Compared to baseline, all interventional diets increased mean Lp(a) by 2 to 5 mg/dl. Unsat Fat increased Lp(a) less than Prot with a difference of 1.0 mg/dl (95% CI, −0.5, 2.5; p = 0.196) in whites and 3.7 mg/dl (95% CI, 2.4, 5.0; p
    Electronic ISSN: 1932-6203
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    Post Diagnosis Diet Quality and Colorectal Cancer Survival in Women (2014)
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    In: PLoS ONE
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    Publication Date: 2014-12-16
    Description: by Teresa T. Fung, Rutendo Kashambwa, Kaori Sato, Stephanie E. Chiuve, Charles S. Fuchs, Kana Wu, Edward Giovannucci, Shuji Ogino, Frank B. Hu, Jeffrey A. Meyerhardt Background Dietary factors are known to influence colorectal cancer (CRC) risk, however, their association with CRC survival is unclear. Therefore, we prospectively examined the association between diet quality scores, dietary patterns and colorectal cancer (CRC) survival. Methods 1201 women diagnosed with stage I–III CRC between 1986 and 2008, were followed through 2010. Diet was assessed via a food frequency questionnaire administered at least 6 months after diagnosis. We computed the Alternate Healthy Eating Index-2010 (AHEI-2010), alternate Mediterranean Diet score (aMED) and Dietary Approaches to Stop Hypertension score (DASH) and derived two dietary patterns, Western (unhealthy) and prudent (healthy), by principal component analysis for each woman. Results During follow-up, we documented 435 deaths, including 162 from CRC. After adjusting for potential confounders, only a higher AHEI-2010 score was significantly associated with lower overall mortality (HR comparing extreme quintiles = 0.71, 95% CI 0.52–0.98, p trend = 0.01) as well as borderline significantly with lower risk of CRC mortality by the trend test (HR Q5 vs Q1 = 0.72, 95% CI = 0.43–1.21, p trend = 0.07). When AHEI-2010 components were examined separately, inverse associations for overall mortality were primarily accounted for by moderate alcohol intake (HR comparing abstainers vs 5–15 g/d = 1.30, 95%CI = 1.05–1.61) and lower intake of sugar sweetened beverages and fruit juices combined (HR for each additional serving = 1.11, 95% CI = 1.01–1.23). No other diet quality score or dietary pattern was associated with overall or CRC-specific mortality. Conclusion Higher AHEI-2010 score may be associated with lower overall mortality, moderate alcohol consumption and lower consumption of sugar sweetened beverages and juices combined appeared to account for most of the observed associations.
    Electronic ISSN: 1932-6203
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    Mesothelin Expression in Triple Negative Breast Carcinomas Correlates Significantly with Basal-Like Phenotype, Distant Metastases and Decreased Survival (2014)
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    Publication Date: 2014-12-16
    Description: by Gary Tozbikian, Edi Brogi, Kyuichi Kadota, Jeffrey Catalano, Muzaffar Akram, Sujata Patil, Alice Y. Ho, Jorge S. Reis-Filho, Britta Weigelt, Larry Norton, Prasad S. Adusumilli, Hannah Yong Wen Mesothelin is a cell surface associated antigen expressed on mesothelial cells and in some malignant neoplasms. Mesothelin-targeted therapies are in phase I/II clinical trials. The clinicopathologic and prognostic significance of mesothelin expression in triple negative breast carcinomas (TNBC) has not been fully assessed. We evaluated the expression of mesothelin and of basal markers in tissue microarrays of 226 TNBC and 88 non-TNBC and assessed the clinicopathologic features of mesothelin-expressing breast carcinomas. Furthermore, we investigated the impact of mesothelin expression on the disease-free and overall survival of patients with TNBC. We found that mesothelin expression is significantly more frequent in TNBC than in non-TNBC (36% vs 16%, respectively; p = 0.0006), and is significantly correlated with immunoreactivity for basal keratins, but not for EGFR. Mesothelin-positive and mesothelin-negative TNBC were not significantly different by patients’ race, tumor size, histologic grade, tumor subtype, lymphovascular invasion and lymph node metastases. Patients with mesothelin-positive TNBC were older than patients with mesothelin-negative TNBC, developed more distant metastases with a shorter interval, and had significantly lower overall and disease-free survival. Based on our results, patients with mesothelin-positive TNBC could benefit from mesothelin-targeted therapies.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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    Correction: Human Papillomavirus and Cystic Node Metastasis in Oropharyngeal Cancer and Cancer of Unknown Primary Origin (2014)
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    In: PLoS ONE
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    Publication Date: 2014-12-16
    Description: by The PLOS ONE Staff
    Electronic ISSN: 1932-6203
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    Correction: Tempol, a Superoxide Dismutase Mimetic Agent, Ameliorates Cisplatin-Induced Nephrotoxicity through Alleviation of Mitochondrial Dysfunction in Mice (2014)
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    In: PLoS ONE
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    Publication Date: 2014-12-16
    Description: by The PLOS ONE Staff
    Electronic ISSN: 1932-6203
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    Correction: A New Recombinant BCG Vaccine Induces Specific Th17 and Th1 Effector Cells with Higher Protective Efficacy against Tuberculosis (2014)
    Public Library of Science (PLoS)
    In: PLoS ONE
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    Publication Date: 2014-12-16
    Description: by The PLOS ONE Staff
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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    Temporal Changes in Population Structure of a Marine Planktonic Diatom (2014)
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    Publication Date: 2014-12-16
    Description: by Sylvie V. M. Tesson, Marina Montresor, Gabriele Procaccini, Wiebe H. C. F. Kooistra A prevailing question in phytoplankton research addresses changes of genetic diversity in the face of huge population sizes and apparently unlimited dispersal capabilities. We investigated population genetic structure of the pennate planktonic marine diatom Pseudo-nitzschia multistriata at the LTER station MareChiara in the Gulf of Naples (Italy) over four consecutive years and explored possible changes over seasons and from year to year. A total of 525 strains were genotyped using seven microsatellite markers, for a genotypic diversity of 75.05%, comparable to that found in other Pseudo-nitzschia species. Evidence from Bayesian clustering analysis (BA) identified two genetically distinct clusters, here interpreted as populations, and several strains that could not be assigned with ≥90% probability to either population, here interpreted as putative hybrids. Principal Component Analysis (PCA) recovered these two clusters in distinct clouds with most of the putative hybrids located in-between. Relative proportions of the two populations and the putative hybrids remained similar within years, but changed radically between 2008 and 2009 and between 2010 and 2011, when the 2008-population apparently became the dominant one again. Strains from the two populations are inter-fertile, and so is their offspring. Inclusion of genotypes of parental strains and their offspring shows that the majority of the latter could not be assigned to any of the two parental populations. Therefore, field strains classified by BA as the putative hybrids could be biological hybrids. We hypothesize that P. multistriata population dynamics in the Gulf of Naples follows a meta-population-like model, including establishment of populations by cell inocula at the beginning of each growth season and remixing and dispersal governed by moving and mildly turbulent water masses.
    Electronic ISSN: 1932-6203
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    A Survey of Management Practices That Influence Performance and Welfare of Dairy Calves Reared in Southern Brazil (2014)
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    Publication Date: 2014-12-16
    Description: by Maria J. Hötzel, Cibele Longo, Lucas F. Balcão, Clarissa S. Cardoso, João H. C. Costa Here we report dairy calf management practices used by 242 smallholder family farmers in the South of Brazil. Data were collected via a semi-structured questionnaire with farmers, inspection of the production environment and an in-depth interview with a sample of 26 farmers. Herds had an average of 22.3 lactating cows and an average milk production of 12.7 L/cow/day. Calves were dehorned in 98% of the farms, with a hot iron in 95%. Male calves were castrated in 71% of the farms; methods were surgery (68%), emasculator (29%), or rubber rings (3%). No pain control was used for these interventions. In 51% of the farms all newborn male calves were reared, sold or donated to others; in 35% all newborn males were killed on the farm. Calves were separated from the dam up to 12 h after birth in 78% of the farms, and left to nurse colostrum from the dam without intervention in 55% of the farms. The typical amount of milk fed to calves was 4 L/day until a median age of 75 days. In 40% of the farms milk was provided in a bucket, in 49% with bottles, and in 11% calves suckled from a cow. Solid feeding in the milk-feeding period started at a median age of 10 days. Calves were housed individually in 70% of the farms; in 81% of the farms calves were housed in indoor pens, in 6% in outdoor hutches and in 13% they were kept on pasture. Diarrhoea was reported as the main cause of calf mortality in 71% of the farms. Farmers kept no records of calf disease, mortality, or use of medicines. Changing the scenario identified in this survey is essential to support the sustainable development of dairy production, an activity of great economic and social relevance for the region.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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    Planning Study of Flattening Filter Free Beams for Volumetric Modulated Arc Therapy in Squamous Cell Carcinoma of the Scalp (2014)
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    In: PLoS ONE
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    Publication Date: 2014-12-16
    Description: by Youqun Lai, Liwan Shi, Qin Lin, Lirong Fu, Huiming Ha Purpose Flattening filter free (FFF) beams show the potential for a higher dose rate and lower peripheral dose. We investigated the planning study of FFF beams with their role for volumetric modulated arc therapy (VMAT) in squamous cell carcinoma of the scalp. Methods and Materials One patient with squamous cell carcinoma which had involvement of entire scalp was subjected to VMAT using TrueBeam linear accelerator. As it was a rare skin malignancy, CT data of 7 patients with brain tumors were also included in this study, and their entire scalps were outlined as target volumes. Three VMAT plans were employed with RapidArc form: two half-field full-arcs VMAT using 6 MV standard beams (HFF-VMAT-FF), eight half-field quarter-arcs VMAT using 6 MV standard beams (HFQ-VMAT-FF), and HFQ-VMAT using FFF beams (HFQ-VMAT-FFF). Prescribed dose was 25×2 Gy (50 Gy). Plan quality and efficiency were assessed for all plans. Results There were no statistically significant differences among the three VMAT plans in target volume coverage, conformity, and homogeneity. For HFQ-VMAT-FF plans, there was a significant decrease by 12.6% in the mean dose to the brain compared with HFF-VMAT-FF. By the use of FFF beams, the mean dose to brain in HFQ-VMAT-FFF plans was further decreased by 7.4% compared with HFQ-VMAT-FF. Beam delivery times were similar for each technique. Conclusions The HFQ-VMAT-FF plans showed the superiority in dose distributions compared with HFF-VMAT-FF. HFQ-VMAT-FFF plans might provide further normal tissue sparing, particularly in the brain, showing their potential for radiation therapy in squamous cell carcinoma of the scalp.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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    Light-Promoted Rhodopsin Expression and Starvation Survival in the Marine Dinoflagellate Oxyrrhis marina (2014)
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    Publication Date: 2014-12-16
    Description: by Zhiling Guo, Huan Zhang, Senjie Lin The discovery of microbial rhodopsins in marine proteobacteria changed the dogma that photosynthesis is the only pathway to use the solar energy for biological utilization in the marine environment. Although homologs of these rhodopsins have been identified in dinoflagellates, the diversity of the encoding genes and their physiological roles remain unexplored. As an initial step toward addressing the gap, we conducted high-throughput transcriptome sequencing on Oxyrrhis marina to retrieve rhodopsin transcripts, rapid amplification of cDNA ends to isolate full-length cDNAs of dominant representatives, and quantitative reverse-transcription PCR to investigate their expression under varying conditions. Our phylogenetic analyses showed that O . marina contained both the proton-pumping type (PR) and sensory type (SR) rhodopsins, and the transcriptome data showed that the PR type dominated over the SR type. We compared rhodopsin gene expression for cultures kept under light: dark cycle and continuous darkness in a time course of 24 days without feeding. Although both types of rhodopsin were expressed under the two conditions, the expression levels of PR were much higher than SR, consistent with the transcriptomic data. Furthermore, relative to cultures kept in the dark, rhodopsin expression levels and cell survival rate were both higher in cultures grown in the light. This is the first report of light-dependent promotion of starvation survival and concomitant promotion of PR expression in a eukaryote. While direct evidence needs to come from functional test on rhodopsins in vitro or gene knockout/knockdown experiments, our results suggest that the proton-pumping rhodopsin might be responsible for the light-enhanced survival of O . marina , as previously demonstrated in bacteria.
    Electronic ISSN: 1932-6203
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    Comparison of Modic Changes in the Lumbar and Cervical Spine, in 3167 Patients with and without Spinal Pain (2014)
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    Publication Date: 2014-12-16
    Description: by Li Sheng-yun, Suyou Letu, Chen Jian, Maiwulanjiang Mamuti, Liu Jun-hui, Shan Zhi, Wang Chong-yan, Fan Shunwu, Fengdong Zhao Background Context There are few comparisons of Modic changes (MCs) in the lumbar and cervical spine. Purpose Compare the prevalence of MCs in the lumbar and cervical spine, and determine how MC prevalence depends on spinal pain, age, disc degeneration, spinal level, and the presence or absence of kyphosis. Study Design Retrospective clinical survey. Materials and Methods Magnetic resonance images (MRIs) were compared from five patient groups: 1. 1223 patients with low-back pain/radiculopathy only; 2. 1023 patients with neck pain/radiculopathy only; 3. 497 patients with concurrent low-back and neck symptoms; 4. 304 asymptomatic subjects with lumbar MRIs; and 5. 120 asymptomatic subjects with cervical MRIs. Results The prevalence of MCs was higher in those with spinal pain than in those without, both in the lumbar spine (21.0% vs 10.5%) and cervical spine (8.8% vs 3.3%). Type II MCs were most common and Type III were least common in all groups. The prevalence of lumbar MCs in people with back pain was little affected by the presence of concurrent neck pain, and the same was true for the prevalence of cervical MCs in people with neck pain with or without concurrent back pain. When symptomatic patients were reclassified into two groups (back pain, neck pain), the prevalence of lumbar MCs in people with back pain was greater than that of cervical MCs in people with neck pain. The prevalence of lumbar and cervical MCs increased with age, disc degeneration, (descending) spinal level, and increased kyphosis. Conclusions There is a significantly higher prevalence of MCs in patients with back and neck pain. The reported association with increased kyphosis (flat back) is novel.
    Electronic ISSN: 1932-6203
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    Magnetic resonance tomography using elongated transmitter and in-loop receiver arrays for time-efficient 2-D imaging of subsurface aquifer structures (2014)
    Oxford University Press
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    Publication Date: 2014-12-17
    Description: Surface nuclear magnetic resonance (surface-NMR) is a promising technique for exploring shallow subsurface aquifer structures. Surface-NMR can be applied in environments that are characterized as a 1-D layered Earth. The technique utilizes a single loop and is referred to as magnetic resonance sounding. The technique referred to as magnetic resonance tomography (MRT) allows complex 2-D aquifer structures to be explored. Currently, MRT requires multiple loops and a roll along measurement scheme, which causes long survey time. We propose a loop layout using an elongated transmitter and an in-loop receiver arrays (ETRA) to conduct a 2-D survey with just one measurement. We present a comprehensive comparison between the new layout and the common approaches based on sensitivity and resolution analyses and show synthetic and field data. The results show that ETRA generates subsurface images at sufficient resolution with significantly lower survey times than other loop layouts.
    Keywords: Geomagnetism, Rock Magnetism and Palaeomagnetism
    Print ISSN: 0956-540X
    Electronic ISSN: 1365-246X
    Topics: Geosciences
    Published by Oxford University Press on behalf of The Deutsche Geophysikalische Gesellschaft (DGG) and the Royal Astronomical Society (RAS).
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    Integrated velocity field from ground and satellite geodetic techniques: application to Arenal volcano (2014)
    Oxford University Press
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    Publication Date: 2014-12-17
    Description: Measurements of ground deformation can be used to identify and interpret geophysical processes occurring at volcanoes. Most studies rely on a single geodetic technique, or fit a geophysical model to the results of multiple geodetic techniques. Here we present a methodology that combines GPS, Total Station measurements and InSAR into a single reference frame to produce an integrated 3-D geodetic velocity surface without any prior geophysical assumptions. The methodology consists of five steps: design of the network, acquisition and processing of the data, spatial integration of the measurements, time series computation and finally the integration of spatial and temporal measurements. The most significant improvements of this method are (1) the reduction of the required field time, (2) the unambiguous detection of outliers, (3) an increased measurement accuracy and (4) the construction of a 3-D geodetic velocity field. We apply this methodology to ongoing motion on Arenal's western flank. Integration of multiple measurement techniques at Arenal volcano revealed a deformation field that is more complex than that described by individual geodetic techniques, yet remains consistent with previous studies. This approach can be applied to volcano monitoring worldwide and has the potential to be extended to incorporate other geodetic techniques and to study transient deformation.
    Keywords: Gravity, Geodesy and Tides
    Print ISSN: 0956-540X
    Electronic ISSN: 1365-246X
    Topics: Geosciences
    Published by Oxford University Press on behalf of The Deutsche Geophysikalische Gesellschaft (DGG) and the Royal Astronomical Society (RAS).
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    Galactic outflow and diffuse gas properties at z 〉= 1 using different baryonic feedback models (2014)
    Oxford University Press
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    Publication Date: 2014-12-17
    Description: We measure and quantify properties of galactic outflows and diffuse gas at z ≥ 1 in cosmological hydrodynamical simulations. Our novel subresolution model, Multi-Phase Particle Integrator (MUPPI), implements supernova feedback using fully local gas properties, where the wind velocity and mass loading are not given as input. We find the following trends at z  = 2 by analysing central galaxies having a stellar mass higher than 10 9 M . The outflow velocity and mass outflow rate ( $\dot{M}_{\rm out}$ ) exhibit positive correlations with galaxy mass and with the star formation rate (SFR). However, most of the relations present a large scatter. The outflow mass loading factor () is between 0.2 and 10. The comparison effective model generates a constant outflow velocity, and a negative correlation of with halo mass. The number fraction of galaxies where outflow is detected decreases at lower redshifts, but remains more than 80 per cent over z  = 1–5. The outflow velocity correlation with SFR becomes flatter at z  = 1, and displays a negative correlation with halo mass in massive galaxies. Our study demonstrates that both the MUPPI and effective models produce significant outflows at ~1/10 of the virial radius; at the same time shows that the properties of outflows generated can be different from the input speed and mass loading in the effective model. Our MUPPI model, using local properties of gas in the subresolution recipe, is able to develop galactic outflows whose properties correlate with global galaxy properties , and consistent with observations.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
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    Multiplex sequencing of pooled mitochondrial genomes--a crucial step toward biodiversity analysis using mito-metagenomics (2014)
    Oxford University Press
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    Publication Date: 2014-12-17
    Description: The advent in high-throughput-sequencing (HTS) technologies has revolutionized conventional biodiversity research by enabling parallel capture of DNA sequences possessing species-level diagnosis. However, polymerase chain reaction (PCR)-based implementation is biased by the efficiency of primer binding across lineages of organisms. A PCR-free HTS approach will alleviate this artefact and significantly improve upon the multi-locus method utilizing full mitogenomes. Here we developed a novel multiplex sequencing and assembly pipeline allowing for simultaneous acquisition of full mitogenomes from pooled animals without DNA enrichment or amplification. By concatenating assemblies from three de novo assemblers, we obtained high-quality mitogenomes for all 49 pooled taxa, with 36 species 〉15 kb and the remaining 〉10 kb, including 20 complete mitogenomes and nearly all protein coding genes (99.6%). The assembly quality was carefully validated with Sanger sequences, reference genomes and conservativeness of protein coding genes across taxa. The new method was effective even for closely related taxa, e.g. three Drosophila spp., demonstrating its broad utility for biodiversity research and mito-phylogenomics. Finally, the in silico simulation showed that by recruiting multiple mito-loci, taxon detection was improved at a fixed sequencing depth. Combined, these results demonstrate the plausibility of a multi-locus mito-metagenomics approach as the next phase of the current single-locus metabarcoding method.
    Keywords: Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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    Easy quantitative assessment of genome editing by sequence trace decomposition (2014)
    Oxford University Press
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    Publication Date: 2014-12-17
    Description: The efficacy and the mutation spectrum of genome editing methods can vary substantially depending on the targeted sequence. A simple, quick assay to accurately characterize and quantify the induced mutations is therefore needed. Here we present TIDE, a method for this purpose that requires only a pair of PCR reactions and two standard capillary sequencing runs. The sequence traces are then analyzed by a specially developed decomposition algorithm that identifies the major induced mutations in the projected editing site and accurately determines their frequency in a cell population. This method is cost-effective and quick, and it provides much more detailed information than current enzyme-based assays. An interactive web tool for automated decomposition of the sequence traces is available. TIDE greatly facilitates the testing and rational design of genome editing strategies.
    Keywords: Targeted gene modification
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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    Accurate ab initio prediction of NMR chemical shifts of nucleic acids and nucleic acids/protein complexes (2014)
    Oxford University Press
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    Publication Date: 2014-12-17
    Description: NMR chemical shift predictions based on empirical methods are nowadays indispensable tools during resonance assignment and 3D structure calculation of proteins. However, owing to the very limited statistical data basis, such methods are still in their infancy in the field of nucleic acids, especially when non-canonical structures and nucleic acid complexes are considered. Here, we present an ab initio approach for predicting proton chemical shifts of arbitrary nucleic acid structures based on state-of-the-art fragment-based quantum chemical calculations. We tested our prediction method on a diverse set of nucleic acid structures including double-stranded DNA, hairpins, DNA/protein complexes and chemically-modified DNA. Overall, our quantum chemical calculations yield highly/very accurate predictions with mean absolute deviations of 0.3–0.6 ppm and correlation coefficients ( r 2 ) usually above 0.9. This will allow for identifying misassignments and validating 3D structures. Furthermore, our calculations reveal that chemical shifts of protons involved in hydrogen bonding are predicted significantly less accurately. This is in part caused by insufficient inclusion of solvation effects. However, it also points toward shortcomings of current force fields used for structure determination of nucleic acids. Our quantum chemical calculations could therefore provide input for force field optimization.
    Keywords: Nucleic acid structure, Protein-nucleic acid interaction
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    Electronic ISSN: 1362-4962
    Topics: Biology
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    Synthesis, biophysical properties and biological activity of second generation antisense oligonucleotides containing chiral phosphorothioate linkages (2014)
    Oxford University Press
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    Publication Date: 2014-12-17
    Description: Bicyclic oxazaphospholidine monomers were used to prepare a series of phosphorothioate (PS)-modified gapmer antisense oligonucleotides (ASOs) with control of the chirality of each of the PS linkages within the 10-base gap. The stereoselectivity was determined to be 98% for each coupling. The objective of this work was to study how PS chirality influences biophysical and biological properties of the ASO including binding affinity ( T m ), nuclease stability, activity in vitro and in vivo , RNase H activation and cleavage patterns (both human and E. coli ) in a gapmer context. Compounds that had nine or more Sp-linkages in the gap were found to be poorly active in vitro , while compounds with uniform Rp-gaps exhibited activity very similar to that of the stereo-random parent ASOs. Conversely, when tested in vivo , the full Rp-gap compound was found to be quickly metabolized resulting in low activity. A total of 31 ASOs were prepared with control of the PS chirally of each linkage within the gap in an attempt to identify favorable Rp/Sp positions. We conclude that a mix of Rp and Sp is required to achieve a balance between good activity and nuclease stability.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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    qDNAmod: a statistical model-based tool to reveal intercellular heterogeneity of DNA modification from SMRT sequencing data (2014)
    Oxford University Press
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    Publication Date: 2014-12-17
    Description: In an isogenic cell population, phenotypic heterogeneity among individual cells is common and critical for survival of the population under different environment conditions. DNA modification is an important epigenetic factor that can regulate phenotypic heterogeneity. The single molecule real-time (SMRT) sequencing technology provides a unique platform for detecting a wide range of DNA modifications, including N6-methyladenine (6-mA), N4-methylcytosine (4-mC) and 5-methylcytosine (5-mC). Here we present qDNAmod, a novel bioinformatic tool for genome-wide quantitative profiling of intercellular heterogeneity of DNA modification from SMRT sequencing data. It is capable of estimating proportion of isogenic haploid cells, in which the same loci of the genome are differentially modified. We tested the reliability of qDNAmod with the SMRT sequencing data of Streptococcus pneumoniae strain ST556. qDNAmod detected extensive intercellular heterogeneity of DNA methylation (6-mA) in a clonal population of ST556. Subsequent biochemical analyses revealed that the recognition sequences of two type I restriction–modification (R-M) systems are responsible for the intercellular heterogeneity of DNA methylation initially identified by qDNAmod. qDNAmod thus represents a valuable tool for studying intercellular phenotypic heterogeneity from genome-wide DNA modification.
    Keywords: Nucleic acid modification, Computational Methods
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    Constrained transcription factor spacing is prevalent and important for transcriptional control of mouse blood cells (2014)
    Oxford University Press
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    Publication Date: 2014-12-17
    Description: Combinatorial transcription factor (TF) binding is essential for cell-type-specific gene regulation. However, much remains to be learned about the mechanisms of TF interactions, including to what extent constrained spacing and orientation of interacting TFs are critical for regulatory element activity. To examine the relative prevalence of the ‘enhanceosome’ versus the ‘TF collective’ model of combinatorial TF binding, a comprehensive analysis of TF binding site sequences in large scale datasets is necessary. We developed a motif-pair discovery pipeline to identify motif co-occurrences with preferential distance(s) between motifs in TF-bound regions. Utilizing a compendium of 289 mouse haematopoietic TF ChIP-seq datasets, we demonstrate that haematopoietic-related motif-pairs commonly occur with highly conserved constrained spacing and orientation between motifs. Furthermore, motif clustering revealed specific associations for both heterotypic and homotypic motif-pairs with particular haematopoietic cell types. We also showed that disrupting the spacing between motif-pairs significantly affects transcriptional activity in a well-known motif-pair—E-box and GATA, and in two previously unknown motif-pairs with constrained spacing—Ets and Homeobox as well as Ets and E-box. In this study, we provide evidence for widespread sequence-specific TF pair interaction with DNA that conforms to the ‘enhanceosome’ model, and furthermore identify associations between specific haematopoietic cell-types and motif-pairs.
    Keywords: Computational Methods
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    In silico prediction of splice-altering single nucleotide variants in the human genome (2014)
    Oxford University Press
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    Publication Date: 2014-12-17
    Description: In silico tools have been developed to predict variants that may have an impact on pre-mRNA splicing. The major limitation of the application of these tools to basic research and clinical practice is the difficulty in interpreting the output. Most tools only predict potential splice sites given a DNA sequence without measuring splicing signal changes caused by a variant. Another limitation is the lack of large-scale evaluation studies of these tools. We compared eight in silico tools on 2959 single nucleotide variants within splicing consensus regions (scSNVs) using receiver operating characteristic analysis. The Position Weight Matrix model and MaxEntScan outperformed other methods. Two ensemble learning methods, adaptive boosting and random forests, were used to construct models that take advantage of individual methods. Both models further improved prediction, with outputs of directly interpretable prediction scores. We applied our ensemble scores to scSNVs from the Catalogue of Somatic Mutations in Cancer database. Analysis showed that predicted splice-altering scSNVs are enriched in recurrent scSNVs and known cancer genes. We pre-computed our ensemble scores for all potential scSNVs across the human genome, providing a whole genome level resource for identifying splice-altering scSNVs discovered from large-scale sequencing studies.
    Keywords: RNA characterisation and manipulation, Computational Methods
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    AGO2 and SETDB1 cooperate in promoter-targeted transcriptional silencing of the androgen receptor gene (2014)
    Oxford University Press
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    Publication Date: 2014-12-17
    Description: In mammals, RNA interference is primarily a post-transcriptional mechanism. Evidence has accumulated for additional role in transcriptional gene silencing (TGS) but the question for a good paradigm for small interfering antigene RNA (agRNA)-induced chromatin modification remains unanswered. Here, we show that SETDB1, a histone H3-lysine 9 (H3K9)-specific methyltransferase, cooperates with Argonaute-2 (AGO2) and plays an essential role in agRNA-induced TGS. The androgen receptor ( AR ) gene was transcriptionally silenced by agRNA targeted to its promoter, and we show that this repression was mitigated by knockdown of SETDB1 or AGO2 . Chromatin immunoprecipitation demonstrated that agRNA-driven AGO2 was first targeted to the AR promoter, followed by SETDB1. SIN3A and HDAC1/2, the components of the SIN3-HDAC complex, immunoprecipitated with SETDB1, and localized at the agRNA-targeted promoter. Agreeing with the presence of SETDB1, trimethyl-H3K9 was enriched in the AR promoter. Both EZH2 and trimethyl-H3K27 were also present in the targeted locus; accordingly, EZH2 immunoprecipitated with SETDB1. DNA methylation level was not significantly changed, suggesting the absence of de novo methylating activity in agRNA-induced AR promoter. Our results demonstrate that SETDB1, together with AGO2, plays an essential role in TGS through recruiting chromatin remodeler and/or other modifiers, consequently creating a repressive chromatin milieu at the targeted promoter.
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    The TCF C-clamp DNA binding domain expands the Wnt transcriptome via alternative target recognition (2014)
    Oxford University Press
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    Publication Date: 2014-12-17
    Description: LEF/TCFs direct the final step in Wnt/β-catenin signalling by recruiting β-catenin to genes for activation of transcription. Ancient, non-vertebrate TCFs contain two DNA binding domains, a High Mobility Group box for recognition of the Wnt Response Element (WRE; 5'-CTTTGWWS-3') and the C-clamp domain for recognition of the GC-rich Helper motif (5'-RCCGCC-3'). Two vertebrate TCFs (TCF-1/TCF7 and TCF-4/TCF7L2) use the C-clamp as an alternatively spliced domain to regulate cell-cycle progression, but how the C-clamp influences TCF binding and activity genome-wide is not known. Here, we used a doxycycline inducible system with ChIP-seq to assess how the C-clamp influences human TCF1 binding genome-wide. Metabolic pulse-labeling of nascent RNA with 4'Thiouridine was used with RNA-seq to connect binding to the Wnt transcriptome. We find that the C-clamp enables targeting to a greater number of gene loci for stronger occupancy and transcription regulation. The C-clamp uses Helper sites concurrently with WREs for gene targeting, but it also targets TCF1 to sites that do not have readily identifiable canonical WREs. The coupled ChIP-seq/4'Thiouridine-seq analysis identified new Wnt target genes, including additional regulators of cell proliferation. Thus, C-clamp containing isoforms of TCFs are potent transcriptional regulators with an expanded transcriptome directed by C-clamp-Helper site interactions.
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    Inference of interactions between chromatin modifiers and histone modifications: from ChIP-Seq data to chromatin-signaling (2014)
    Oxford University Press
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    Publication Date: 2014-12-17
    Description: Chromatin modifiers and histone modifications are components of a chromatin-signaling network involved in transcription and its regulation. The interactions between chromatin modifiers and histone modifications are often unknown, are based on the analysis of few genes or are studied in vitro . Here, we apply computational methods to recover interactions between chromatin modifiers and histone modifications from genome-wide ChIP-Seq data. These interactions provide a high-confidence backbone of the chromatin-signaling network. Many recovered interactions have literature support; others provide hypotheses about yet unknown interactions. We experimentally verified two of these predicted interactions, leading to a link between H4K20me1 and members of the Polycomb Repressive Complexes 1 and 2. Our results suggest that our computationally derived interactions are likely to lead to novel biological insights required to establish the connectivity of the chromatin-signaling network involved in transcription and its regulation.
    Keywords: Genomics
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    Profiling small RNA reveals multimodal substructural signals in a Boltzmann ensemble (2014)
    Oxford University Press
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    Publication Date: 2014-12-17
    Description: As the biomedical impact of small RNAs grows, so does the need to understand competing structural alternatives for regions of functional interest. Suboptimal structure analysis provides significantly more RNA base pairing information than a single minimum free energy prediction. Yet computational enhancements like Boltzmann sampling have not been fully adopted by experimentalists since identifying meaningful patterns in this data can be challenging. Profiling is a novel approach to mining RNA suboptimal structure data which makes the power of ensemble-based analysis accessible in a stable and reliable way. Balancing abstraction and specificity, profiling identifies significant combinations of base pairs which dominate low-energy RNA secondary structures. By design, critical similarities and differences are highlighted, yielding crucial information for molecular biologists. The code is freely available via http://gtfold.sourceforge.net/profiling.html .
    Keywords: Nucleic acid structure, Computational Methods
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    EDITORIAL: NAR AWARDS 2014 (2014)
    Oxford University Press
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    Publication Date: 2014-12-17
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    DNA cleavage by CgII and NgoAVII requires interaction between N- and R-proteins and extensive nucleotide hydrolysis (2014)
    Oxford University Press
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    Publication Date: 2014-12-17
    Description: The stress-sensitive restriction-modification (RM) system CglI from Corynebacterium glutamicum and the homologous NgoAVII RM system from Neisseria gonorrhoeae FA1090 are composed of three genes: a DNA methyltransferase (M.CglI and M.NgoAVII), a putative restriction endonuclease (R.CglI and R.NgoAVII, or R-proteins) and a predicted DEAD-family helicase/ATPase (N.CglI and N.NgoAVII or N-proteins). Here we report a biochemical characterization of the R- and N-proteins. Size-exclusion chromatography and SAXS experiments reveal that the isolated R.CglI, R.NgoAVII and N.CglI proteins form homodimers, while N.NgoAVII is a monomer in solution. Moreover, the R.CglI and N.CglI proteins assemble in a complex with R 2 N 2 stoichiometry. Next, we show that N-proteins have ATPase activity that is dependent on double-stranded DNA and is stimulated by the R-proteins. Functional ATPase activity and extensive ATP hydrolysis (~170 ATP/s/monomer) are required for site-specific DNA cleavage by R-proteins. We show that ATP-dependent DNA cleavage by R-proteins occurs at fixed positions (6–7 nucleotides) downstream of the asymmetric recognition sequence 5'-GCCGC-3'. Despite similarities to both Type I and II restriction endonucleases, the CglI and NgoAVII enzymes may employ a unique catalytic mechanism for DNA cleavage.
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    Diverse cell stresses induce unique patterns of tRNA up- and down-regulation: tRNA-seq for quantifying changes in tRNA copy number (2014)
    Oxford University Press
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    Publication Date: 2014-12-17
    Description: Emerging evidence points to roles for tRNA modifications and tRNA abundance in cellular stress responses. While isolated instances of stress-induced tRNA degradation have been reported, we sought to assess the effects of stress on tRNA levels at a systems level. To this end, we developed a next-generation sequencing method that exploits the paucity of ribonucleoside modifications at the 3'-end of tRNAs to quantify changes in all cellular tRNA molecules. Application of this tRNA-seq method to Saccharomyces cerevisiae identified all 76 expressed unique tRNA species out of 295 coded in the yeast genome, including all isoacceptor variants, with highly precise relative (fold-change) quantification of tRNAs. In studies of stress-induced changes in tRNA levels, we found that oxidation (H 2 O 2 ) and alkylation (methylmethane sulfonate, MMS) stresses induced nearly identical patterns of up- and down-regulation for 58 tRNAs. However, 18 tRNAs showed opposing changes for the stresses, which parallels our observation of signature reprogramming of tRNA modifications caused by H 2 O 2 and MMS. Further, stress-induced degradation was limited to only a small proportion of a few tRNA species. With tRNA-seq applicable to any organism, these results suggest that translational control of stress response involves a contribution from tRNA abundance.
    Keywords: Nucleic acid modification, Transcriptome Mapping - Monitoring Gene Expression
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    Rad51/Dmc1 paralogs and mediators oppose DNA helicases to limit hybrid DNA formation and promote crossovers during meiotic recombination (2014)
    Oxford University Press
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    Publication Date: 2014-12-17
    Description: During meiosis programmed DNA double-strand breaks (DSBs) are repaired by homologous recombination using the sister chromatid or the homologous chromosome (homolog) as a template. This repair results in crossover (CO) and non-crossover (NCO) recombinants. Only CO formation between homologs provides the physical linkages guiding correct chromosome segregation, which are essential to produce healthy gametes. The factors that determine the CO/NCO decision are still poorly understood. Using Schizosaccharomyces pombe as a model we show that the Rad51/Dmc1-paralog complexes Rad55-Rad57 and Rdl1-Rlp1-Sws1 together with Swi5-Sfr1 play a major role in antagonizing both the FANCM-family DNA helicase/translocase Fml1 and the RecQ-type DNA helicase Rqh1 to limit hybrid DNA formation and promote Mus81-Eme1-dependent COs. A common attribute of these protein complexes is an ability to stabilize the Rad51/Dmc1 nucleoprotein filament, and we propose that it is this property that imposes constraints on which enzymes gain access to the recombination intermediate, thereby controlling the manner in which it is processed and resolved.
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    Landscape of target:guide homology effects on Cas9-mediated cleavage (2014)
    Oxford University Press
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    Publication Date: 2014-12-17
    Description: To study target sequence specificity, selectivity, and reaction kinetics of Streptococcus pyogenes Cas9 activity, we challenged libraries of random variant targets with purified Cas9::guide RNA complexes in vitro . Cleavage kinetics were nonlinear, with a burst of initial activity followed by slower sustained cleavage. Consistent with other recent analyses of Cas9 sequence specificity, we observe considerable (albeit incomplete) impairment of cleavage for targets mutated in the PAM sequence or in ‘seed’ sequences matching the proximal 8 bp of the guide. A second target region requiring close homology was located at the other end of the guide::target duplex (positions 13–18 relative to the PAM). Sequences flanking the guide+PAM region had measurable (albeit modest) effects on cleavage. In addition, the first-base Guanine constraint commonly imposed by gRNA expression systems has little effect on overall cleavage efficiency. Taken together, these studies provide an in vitro understanding of the complexities of Cas9–gRNA interaction and cleavage beyond the general paradigm of site determination based on the ‘seed’ sequence and PAM.
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    Identification of tri-phosphatase activity in the biogenesis of retroviral microRNAs and RNAP III-generated shRNAs (2014)
    Oxford University Press
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    Publication Date: 2014-12-17
    Description: Transcripts possessing a 5'-triphosphate are a hallmark of viral transcription and can trigger the host antiviral response. 5'-triphosphates are also found on common host transcripts transcribed by RNA polymerase III (RNAP III), yet how these transcripts remain non-immunostimulatory is incompletely understood. Most microRNAs (miRNAs) are 5'-monophosphorylated as a result of sequential endonucleolytic processing by Drosha and Dicer from longer RNA polymerase II (RNAP II)-transcribed primary transcripts. In contrast, bovine leukemia virus (BLV) expresses subgenomic RNAP III transcripts that give rise to miRNAs independent of Drosha processing. Here, we demonstrate that each BLV pre-miRNA is directly transcribed by RNAP III from individual, compact RNAP III type II genes. Thus, similar to manmade RNAP III-generated short hairpin RNAs (shRNAs), the BLV pre-miRNAs are initially 5'-triphosphorylated. Nonetheless, the derivative 5p miRNAs and shRNA-generated 5p small RNAs (sRNAs) possess a 5'-monophosphate. Our enzymatic characterization and small RNA sequencing data demonstrate that BLV 5p miRNAs are co-terminal with 5'-triphosphorylated miRNA precursors (pre-miRNAs). Thus, these results identify a 5'-tri-phosphatase activity that is involved in the biogenesis of BLV miRNAs and shRNA-generated sRNAs. This work advances our understanding of retroviral miRNA and shRNA biogenesis and may have implications regarding the immunostimulatory capacity of RNAP III transcripts.
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    A bottom-up characterization of transfer functions for synthetic biology designs: lessons from enzymology (2014)
    Oxford University Press
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    Publication Date: 2014-12-17
    Description: Within the field of synthetic biology, a rational design of genetic parts should include a causal understanding of their input-output responses—the so-called transfer function—and how to tune them. However, a commonly adopted strategy is to fit data to Hill-shaped curves without considering the underlying molecular mechanisms. Here we provide a novel mathematical formalization that allows prediction of the global behavior of a synthetic device by considering the actual information from the involved biological parts. This is achieved by adopting an enzymology-like framework, where transfer functions are described in terms of their input affinity constant and maximal response. As a proof of concept, we characterize a set of Lux homoserine-lactone-inducible genetic devices with different levels of Lux receptor and signal molecule. Our model fits the experimental results and predicts the impact of the receptor's ribosome-binding site strength, as a tunable parameter that affects gene expression. The evolutionary implications are outlined.
    Keywords: Synthetic Biology and Assembly Cloning, Computational Methods
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    Crystal structure of the R-protein of the multisubunit ATP-dependent restriction endonuclease NgoAVII (2014)
    Oxford University Press
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    Publication Date: 2014-12-17
    Description: The restriction endonuclease (REase) NgoAVII is composed of two proteins, R.NgoAVII and N.NgoAVII, and shares features of both Type II restriction enzymes and Type I/III ATP-dependent restriction enzymes (see accompanying paper Zaremba et al. , 2014). Here we present crystal structures of the R.NgoAVII apo-protein and the R.NgoAVII C-terminal domain bound to a specific DNA. R.NgoAVII is composed of two domains: an N-terminal nucleolytic PLD domain; and a C-terminal B3-like DNA-binding domain identified previously in BfiI and EcoRII REases, and in plant transcription factors. Structural comparison of the B3-like domains of R.NgoAVII, EcoRII, BfiI and the plant transcription factors revealed a conserved DNA-binding surface comprised of N- and C-arms that together grip the DNA. The C-arms of R.NgoAVII, EcoRII, BfiI and plant B3 domains are similar in size, but the R.NgoAVII N-arm which makes the majority of the contacts to the target site is much longer. The overall structures of R.NgoAVII and BfiI are similar; however, whilst BfiI has stand-alone catalytic activity, R.NgoAVII requires an auxiliary cognate N.NgoAVII protein and ATP hydrolysis in order to cleave DNA at the target site. The structures we present will help formulate future experiments to explore the molecular mechanisms of intersubunit crosstalk that control DNA cleavage by R.NgoAVII and related endonucleases.
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    Synergetic regulation of translational reading-frame switch by ligand-responsive RNAs in mammalian cells (2014)
    Oxford University Press
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    Publication Date: 2014-12-17
    Description: Distinct translational initiation mechanisms between prokaryotes and eukaryotes limit the exploitation of prokaryotic riboswitch repertoire for regulatory RNA circuit construction in mammalian application. Here, we explored programmed ribosomal frameshifting (PRF) as the regulatory gene expression platform for engineered ligand-responsive RNA devices in higher eukaryotes. Regulation was enabled by designed ligand-dependent conformational rearrangements of the two cis-acting RNA motifs of opposite activity in -1 PRF. Particularly, RNA elements responsive to trans-acting ligands can be tailored to modify co-translational RNA refolding dynamics of a hairpin upstream of frameshifting site to achieve reversible and adjustable -1 PRF attenuating activity. Combined with a ligand-responsive stimulator, synthetic RNA devices for synergetic translational-elongation control of gene expression can be constructed. Due to the similarity between co-transcriptional RNA hairpin folding and co-translational RNA hairpin refolding, the RNA-responsive ligand repertoire provided in prokaryotic systems thus becomes accessible to gene-regulatory circuit construction for synthetic biology application in mammalian cells.
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    DNA repair inhibition by UVA photoactivated fluoroquinolones and vemurafenib (2014)
    Oxford University Press
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    Publication Date: 2014-12-17
    Description: Cutaneous photosensitization is a common side effect of drug treatment and can be associated with an increased skin cancer risk. The immunosuppressant azathioprine, the fluoroquinolone antibiotics and vemurafenib—a BRAF inhibitor used to treat metastatic melanoma—are all recognized clinical photosensitizers. We have compared the effects of UVA radiation on cultured human cells treated with 6-thioguanine (6-TG, a DNA-embedded azathioprine surrogate), the fluoroquinolones ciprofloxacin and ofloxacin and vemurafenib. Despite widely different structures and modes of action, each of these drugs potentiated UVA cytotoxicity. UVA photoactivation of 6-TG, ciprofloxacin and ofloxacin was associated with the generation of singlet oxygen that caused extensive protein oxidation. In particular, these treatments were associated with damage to DNA repair proteins that reduced the efficiency of nucleotide excision repair. Although vemurafenib was also highly phototoxic to cultured cells, its effects were less dependent on singlet oxygen. Highly toxic combinations of vemurafenib and UVA caused little protein carbonylation but were nevertheless inhibitory to nucleotide excision repair. Thus, for three different classes of drugs, photosensitization by at least two distinct mechanisms is associated with reduced protection against potentially mutagenic and carcinogenic DNA damage.
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    Replication-guided nucleosome packing and nucleosome breathing expedite the formation of dense arrays (2014)
    Oxford University Press
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    Publication Date: 2014-12-17
    Description: The first level of genome packaging in eukaryotic cells involves the formation of dense nucleosome arrays, with DNA coverage near 90% in yeasts. How cells achieve such high coverage within a short time, e.g. after DNA replication, remains poorly understood. It is known that random sequential adsorption of impenetrable particles on a line reaches high density extremely slowly, due to a jamming phenomenon. The nucleosome-shifting action of remodeling enzymes has been proposed as a mechanism to resolve such jams. Here, we suggest two biophysical mechanisms which assist rapid filling of DNA with nucleosomes, and we quantitatively characterize these mechanisms within mathematical models. First, we show that the ‘softness’ of nucleosomes, due to nucleosome breathing and stepwise nucleosome assembly, significantly alters the filling behavior, speeding up the process relative to ‘hard’ particles with fixed, mutually exclusive DNA footprints. Second, we explore model scenarios in which the progression of the replication fork could eliminate nucleosome jamming, either by rapid filling in its wake or via memory of the parental nucleosome positions. Taken together, our results suggest that biophysical effects promote rapid nucleosome filling, making the reassembly of densely packed nucleosomes after DNA replication a simpler task for cells than was previously thought.
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    Loss of loop adenines alters human telomere d[AG3(TTAG3)3] quadruplex folding (2014)
    Oxford University Press
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    Publication Date: 2014-12-17
    Description: Abasic (AP) lesions are the most frequent type of damages occurring in cellular DNA. Here we describe the conformational effects of AP sites substituted for 2'-deoxyadenosine in the first ( ap7 ), second ( ap13 ) or third ( ap19 ) loop of the quadruplex formed in K + by the human telomere DNA 5'-d[AG 3 (TTAG 3 ) 3 ]. CD spectra and electrophoresis reveal that the presence of AP sites does not hinder the formation of intramolecular quadruplexes. NMR spectra show that the structural heterogeneity is substantially reduced in ap7 and ap19 as compared to that in the wild-type. These two ( ap7 and ap19 ) sequences are shown to adopt the hybrid-1 and hybrid-2 quadruplex topology, respectively, with AP site located in a propeller-like loop. All three studied sequences transform easily into parallel quadruplex in dehydrating ethanol solution. Thus, the AP site in any loop region facilitates the formation of the propeller loop. Substitution of all adenines by AP sites stabilizes the parallel quadruplex even in the absence of ethanol. Whereas guanines are the major determinants of quadruplex stability, the presence or absence of loop adenines substantially influences quadruplex folding. The naturally occurring adenine-lacking sites in the human telomere DNA can change the quadruplex topology in vivo with potentially vital biological consequences.
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    Specific minor groove solvation is a crucial determinant of DNA binding site recognition (2014)
    Oxford University Press
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    Publication Date: 2014-12-17
    Description: The DNA sequence preferences of nearly all sequence specific DNA binding proteins are influenced by the identities of bases that are not directly contacted by protein. Discrimination between non-contacted base sequences is commonly based on the differential abilities of DNA sequences to allow narrowing of the DNA minor groove. However, the factors that govern the propensity of minor groove narrowing are not completely understood. Here we show that the differential abilities of various DNA sequences to support formation of a highly ordered and stable minor groove solvation network are a key determinant of non-contacted base recognition by a sequence-specific binding protein. In addition, disrupting the solvent network in the non-contacted region of the binding site alters the protein's ability to recognize contacted base sequences at positions 5–6 bases away. This observation suggests that DNA solvent interactions link contacted and non-contacted base recognition by the protein.
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    The topology of Stein fillable manifolds in high dimensions I (2014)
    Oxford University Press
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    Publication Date: 2014-12-17
    Description: We give a bordism-theoretic characterization of those closed almost contact $(2q{+ }1)$ -manifolds (with $q\geq 2$ ) that admit a Stein fillable contact structure. Our method is to apply Eliashberg's $h$ -principle for Stein manifolds in the setting of Kreck's modified surgery. As an application, we show that any simply connected almost contact 7-manifold with torsion-free second homotopy group is Stein fillable. We also discuss the Stein fillability of exotic spheres and examine subcritical Stein fillability.
    Print ISSN: 0024-6115
    Electronic ISSN: 1460-244X
    Topics: Mathematics
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    A vanishing result for a Casson-type instanton invariant (2014)
    Oxford University Press
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    Publication Date: 2014-12-17
    Description: Casson-type invariants emerging from Donaldson theory over certain negative-definite four-manifolds were recently suggested by Teleman. These are defined by an algebraic count of points in a zero-dimensional moduli space of flat instantons. Motivated by the cobordism programme of proving Witten's conjecture, we use a moduli space of ${\rm PU}(2)$ Seiberg–Witten monopoles to exhibit an oriented one-dimensional cobordism of the instanton moduli space to the empty space. The Casson-type invariant must therefore vanish.
    Print ISSN: 0024-6115
    Electronic ISSN: 1460-244X
    Topics: Mathematics
    Published by Oxford University Press
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    A fourth-order model for MEMS with clamped boundary conditions (2014)
    Oxford University Press
    Details
    Publication Date: 2014-12-17
    Description: The dynamical and stationary behaviors of a fourth-order equation in the unit ball with clamped boundary conditions and a singular reaction term are investigated. The equation arises in the modeling of microelectromechanical systems and includes a positive voltage parameter $\lambda$ . It is shown that there is a threshold value $\lambda _* 〉 0$ of the voltage parameter such that no radially symmetric stationary solution exists for $\lambda 〉 \lambda _* $ , while at least two such solutions exist for $\lambda \in (0,\lambda _* )$ . Local and global well-posedness results are obtained for the corresponding hyperbolic and parabolic evolution problems as well as the occurrence of finite time singularities when $\lambda 〉 \lambda _* $ .
    Print ISSN: 0024-6115
    Electronic ISSN: 1460-244X
    Topics: Mathematics
    Published by Oxford University Press
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    Magnetic flux of progenitor stars sets gamma-ray burst luminosity and variability (2014)
    Oxford University Press
    Details
    Publication Date: 2014-12-18
    Description: Long-duration gamma-ray bursts (GRBs) are thought to come from the core collapse of Wolf–Rayet stars. Whereas their stellar masses M * have a rather narrow distribution, the population of GRBs is very diverse, with gamma-ray luminosities L spanning several orders of magnitude. This suggests the existence of a ‘hidden’ stellar variable whose burst-to-burst variation leads to a spread in L . Whatever this hidden variable is, its variation should not noticeably affect the shape of GRB light curves, which display a constant luminosity (in a time-average sense) followed by a sharp drop at the end of the burst seen with Swift /XRT. We argue that such a hidden variable is progenitor star's large-scale magnetic flux. Shortly after the core collapse, most of stellar magnetic flux accumulates near the black hole (BH) and remains there. The flux extracts BH rotational energy and powers jets of roughly a constant luminosity, L j . However, once BH mass accretion rate $\dot{M}$ falls below ~ L j / c 2 , the flux becomes dynamically important and diffuses outwards, with the jet luminosity set by the rapidly declining mass accretion rate, $L_{\rm j}\sim \dot{M}c^2$ . This provides a potential explanation for the sharp end of GRBs and the universal shape of their light curves. During the GRB, gas infall translates spatial variation of stellar magnetic flux into temporal variation of L j . We make use of the deviations from constancy in L j to perform stellar magnetic flux ‘tomography’. Using this method, we infer the presence of magnetized tori in the outer layers of progenitor stars for GRB 920513 and GRB 940210.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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    Blind foreground subtraction for intensity mapping experiments (2014)
    Oxford University Press
    Details
    Publication Date: 2014-12-18
    Description: We make use of a large set of fast simulations of an intensity mapping experiment with characteristics similar to those expected of the Square Kilometre Array in order to study the viability and limits of blind foreground subtraction techniques. In particular, we consider three different approaches: polynomial fitting, principal component analysis (PCA) and independent component analysis (ICA). We review the motivations and algorithms for the three methods, and show that they can all be described, using the same mathematical framework, as different approaches to the blind source separation problem. We study the efficiency of foreground subtraction both in the angular and radial (frequency) directions, as well as the dependence of this efficiency on different instrumental and modelling parameters. For well-behaved foregrounds and instrumental effects, we find that foreground subtraction can be successful to a reasonable level on most scales of interest. We also quantify the effect that the cleaning has on the recovered signal and power spectra. Interestingly, we find that the three methods yield quantitatively similar results, with PCA and ICA being almost equivalent.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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    Hot gas in massive haloes drives both mass quenching and environment quenching (2014)
    Oxford University Press
    Details
    Publication Date: 2014-12-18
    Description: Observed galaxies with high stellar masses or in dense environments have low specific star formation rates, i.e. they are quenched. Based on cosmological hydrodynamic simulations that include a prescription where quenching occurs in regions dominated by hot (〉10 5.4  K) gas, we argue that this hot gas quenching in haloes 〉10 12 M drives both mass quenching (i.e. central quenching) and environment quenching (i.e. satellite quenching). These simulations reproduce a broad range of locally observed trends among quenching, halo mass, stellar mass, environment, and distance to halo centre. Mass quenching is independent of environment because ~10 12 –10 13 M ‘mass quenching haloes’ inhabit a large range of environments. On the other hand, environment quenching is independent of stellar mass because galaxies of all stellar masses may live in dense environments as satellites of groups and clusters. As in observations, the quenched fraction of satellites increases with halo mass and decreases with distance to the centre of the group or cluster. We investigate pre-processing in group haloes, ejected former satellites, and hot gas that extends beyond the virial radius. The agreement of our model with key observational trends suggests that hot gas in massive haloes plays a leading role in quenching low-redshift galaxies.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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    Observations of hydroxyl in early-type galaxies (2014)
    Oxford University Press
    Details
    Publication Date: 2014-12-18
    Description: We used Arecibo Observatory and the Green Bank Telescope to observe OH in 12 early-type galaxies with known reservoirs of dense gas. We present three new detections of OH in absorption in the 1667 MHz line. One objective of our survey was to find evidence of molecular outflows, but our sensitivity and the strength of the OH absorption were insufficient to detect outflows. The detected sources have infrared luminosities and dust temperatures among the lowest of any galaxy detected in OH absorption. The ratio L HCN / L CO , a measure of the dense gas fraction in galaxies, is a powerful selector of OH megamasers for galaxies with high infrared luminosity. In early-type galaxies, which have much lower infrared luminosities, L HCN / L CO is also a promising tool for discovering OH, but in absorption rather than in maser emission. In addition to dense molecular gas, a radio continuum source and a favourable line of sight to the observer are likely key factors in detecting OH absorbers.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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    Low-end mass function of the arches cluster (2014)
    Oxford University Press
    Details
    Publication Date: 2014-12-18
    Description: The initial mass function (IMF) of the Arches cluster, which was formed a few million years ago in the harsh environment of the Galactic Centre (GC), has long been a target of interest to those who study the GC and the theory of star formation. The distinct star-forming conditions in the GC might have caused the cluster to have a shallower slope or an elevated lower mass cutoff in its IMF. But its mass function (MF) has been revealed only down to 1–2 M (the lower limit of resolved stars), and the low-end MF of the Arches is still unknown. To estimate the unresolved part of the Arches MF, we have devised a novel photometric method that involves the histogram of pixel intensities in the observed image, which contains information on the unresolved, faint stars. By comparing the pixel intensity histograms (PIHs) of numerous artificial images constructed from model IMFs with the observed PIH, we find that the best-fitting model IMF for the Arches cluster has a cutoff mass less than or similar to 0.1 M and a shape very close to that of the Kroupa MF. Our findings imply that the IMF of the Arches cluster is similar to those found in the Galactic disc.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
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    Correction: Clinical Practice Guidelines and Consensus Statements in Oncology – An Assessment of Their Methodological Quality (2014)
    Public Library of Science (PLoS)
    In: PLoS ONE
    Details
    Publication Date: 2014-12-18
    Description: by The PLOS ONE Staff
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
    Published by Public Library of Science (PLoS)
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