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  • 1
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    Structural basis for selective targeting of leishmanial ribosomes: aminoglycoside derivatives as promising therapeutics (2015)
    Oxford University Press
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    Publication Date: 2015-09-30
    Description: Leishmaniasis comprises an array of diseases caused by pathogenic species of Leishmania , resulting in a spectrum of mild to life-threatening pathologies. Currently available therapies for leishmaniasis include a limited selection of drugs. This coupled with the rather fast emergence of parasite resistance, presents a dire public health concern. Paromomycin (PAR), a broad-spectrum aminoglycoside antibiotic, has been shown in recent years to be highly efficient in treating visceral leishmaniasis (VL)—the life-threatening form of the disease. While much focus has been given to exploration of PAR activities in bacteria, its mechanism of action in Leishmania has received relatively little scrutiny and has yet to be fully deciphered. In the present study we present an X-ray structure of PAR bound to rRNA model mimicking its leishmanial binding target, the ribosomal A-site. We also evaluate PAR inhibitory actions on leishmanial growth and ribosome function, as well as effects on auditory sensory cells, by comparing several structurally related natural and synthetic aminoglycoside derivatives. The results provide insights into the structural elements important for aminoglycoside inhibitory activities and selectivity for leishmanial cytosolic ribosomes, highlighting a novel synthetic derivative, compound 3 , as a prospective therapeutic candidate for the treatment of VL.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 2
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    Hierarchical cosmic shear power spectrum inference (2015)
    Oxford University Press
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    Publication Date: 2015-12-11
    Description: We develop a Bayesian hierarchical modelling approach for cosmic shear power spectrum inference, jointly sampling from the posterior distribution of the cosmic shear field and its (tomographic) power spectra. Inference of the shear power spectrum is a powerful intermediate product for a cosmic shear analysis, since it requires very few model assumptions and can be used to perform inference on a wide range of cosmological models a posteriori without loss of information. We show that joint posterior for the shear map and power spectrum can be sampled effectively by Gibbs sampling, iteratively drawing samples from the map and power spectrum, each conditional on the other. This approach neatly circumvents difficulties associated with complicated survey geometry and masks that plague frequentist power spectrum estimators, since the power spectrum inference provides prior information about the field in masked regions at every sampling step. We demonstrate this approach for inference of tomographic shear E -mode, B -mode and EB -cross power spectra from a simulated galaxy shear catalogue with a number of important features; galaxies distributed on the sky and in redshift with photometric redshift uncertainties, realistic random ellipticity noise for every galaxy and a complicated survey mask. The obtained posterior distributions for the tomographic power spectrum coefficients recover the underlying simulated power spectra for both E - and B -modes.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 3
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    Extreme data compression while searching for new physics (2020)
    Oxford University Press
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    Publication Date: 2020-08-26
    Description: Bringing a high-dimensional data set into science-ready shape is a formidable challenge that often necessitates data compression. Compression has accordingly become a key consideration for contemporary cosmology, affecting public data releases, and reanalyses searching for new physics. However, data compression optimized for a particular model can suppress signs of new physics, or even remove them altogether. We therefore provide a solution for exploring new physics during data compression. In particular, we store additional agnostic compressed data points, selected to enable precise constraints of non-standard physics at a later date. Our procedure is based on the maximal compression of the MOPED algorithm, which optimally filters the data with respect to a baseline model. We select additional filters, based on a generalized principal component analysis, which are carefully constructed to scout for new physics at high precision and speed. We refer to the augmented set of filters as MOPED-PC. They enable an analytic computation of Bayesian Evidence that may indicate the presence of new physics, and fast analytic estimates of best-fitting parameters when adopting a specific non-standard theory, without further expensive MCMC analysis. As there may be large numbers of non-standard theories, the speed of the method becomes essential. Should no new physics be found, then our approach preserves the precision of the standard parameters. As a result, we achieve very rapid and maximally precise constraints of standard and non-standard physics, with a technique that scales well to large dimensional data sets.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press on behalf of The Royal Astronomical Society.
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  • 4
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    BUDHIES - III: the fate of H I and the quenching of galaxies in evolving environments (2016)
    Oxford University Press
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    Publication Date: 2016-07-06
    Description: In a hierarchical Universe clusters grow via the accretion of galaxies from the field, groups and even other clusters. As this happens, galaxies can lose and/or consume their gas reservoirs via different mechanisms, eventually quenching their star formation. We explore the diverse environmental histories of galaxies through a multiwavelength study of the combined effect of ram-pressure stripping and group ‘processing’ in Abell 963, a massive growing cluster at z = 0.2 from the Blind Ultra Deep H i Environmental Survey (BUDHIES). We incorporate hundreds of new optical redshifts (giving a total of 566 cluster members), as well as Subaru and XMM–Newton data from LoCuSS, to identify substructures and evaluate galaxy morphology, star formation activity, and H i content (via H i deficiencies and stacking) out to 3 x R 200 . We find that Abell 963 is being fed by at least seven groups, that contribute to the large number of passive galaxies outside the cluster core. More massive groups have a higher fraction of passive and H i -poor galaxies, while low-mass groups host younger (often interacting) galaxies. For cluster galaxies not associated with groups we corroborate our previous finding that H i gas (if any) is significantly stripped via ram-pressure during their first passage through the intracluster medium, and find mild evidence for a starburst associated with this event. In addition, we find an overabundance of morphologically peculiar and/or star-forming galaxies near the cluster core. We speculate that these arise from the effect of groups passing through the cluster (post-processing). Our study highlights the importance of environmental quenching and the complexity added by evolving environments.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 5
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    Early Science with the Large Millimeter Telescope: COOL BUDHIES I - a pilot study of molecular and atomic gas at z ~= 0.2 (2016)
    Oxford University Press
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    Publication Date: 2016-05-12
    Description: An understanding of the mass build-up in galaxies over time necessitates tracing the evolution of cold gas (molecular and atomic) in galaxies. To that end, we have conducted a pilot study called CO Observations with the LMT of the Blind Ultra-Deep H  i Environment Survey (COOL BUDHIES). We have observed 23 galaxies in and around the two clusters Abell 2192 ( z = 0.188) and Abell 963 ( z = 0.206), where 12 are cluster members and 11 are slightly in the foreground or background, using about 28 total hours on the Redshift Search Receiver on the Large Millimeter Telescope (LMT) to measure the 12 CO J = 1 -〉 0 emission line and obtain molecular gas masses. These new observations provide a unique opportunity to probe both the molecular and atomic components of galaxies as a function of environment beyond the local Universe. For our sample of 23 galaxies, nine have reliable detections (S/N ≥ 3.6) of the 12 CO line, and another six have marginal detections (2.0 〈 S/N 〈 3.6). For the remaining eight targets we can place upper limits on molecular gas masses roughly between 10 9 and 10 10 M . Comparing our results to other studies of molecular gas, we find that our sample is significantly more abundant in molecular gas overall, when compared to the stellar and the atomic gas component, and our median molecular gas fraction lies about 1 above the upper limits of proposed redshift evolution in earlier studies. We discuss possible reasons for this discrepancy, with the most likely conclusion being target selection and Eddington bias.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 6
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    Weak lensing with sizes, magnitudes and shapes (2015)
    Oxford University Press
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    Publication Date: 2015-07-16
    Description: Weak lensing can be observed through a number of effects on the images of distant galaxies; their shapes are sheared, sizes and fluxes (magnitudes) are magnified and positions on the sky are modified by the lensing field. Galaxy shapes probe the shear field whilst size, magnitude and number density probe the convergence field. Both contain cosmological information. In this paper, we are concerned with the magnification of sizes and magnitudes of individual galaxies as a probe of cosmic convergence. We develop a Bayesian approach for inferring the convergence field from measured sizes, magnitudes and redshifts and demonstrate that this inference requires detailed knowledge of the joint distribution of intrinsic sizes and magnitudes. We build a simple parametrized model for the size–magnitude distribution and estimate this distribution for CFHTLenS galaxies. In light of the measured distribution, we show that the typical dispersion on convergence estimation is ~0.8, compared to ~0.38 for shear. We discuss the possibility of physical systematics for magnification (similar to intrinsic alignments for shear) and compute the expected gains in the dark energy figure-of-merit (FoM) from combining magnification with shear for different scenarios regarding systematics: accounting for intrinsic alignments but no systematics for magnification, including magnification could improve the FoM by up to a factor of ~2.5, whilst when accounting for physical systematics in both shear and magnification we anticipate a gain between ~25 and ~65 per cent. The fact that shear and magnification are subject to different systematics makes magnification an attractive complement to any cosmic shear analysis.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 7
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    The sva package for removing batch effects and other unwanted variation in high-throughput experiments (2012)
    Oxford University Press
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    Publication Date: 2012-03-20
    Description: : Heterogeneity and latent variables are now widely recognized as major sources of bias and variability in high-throughput experiments. The most well-known source of latent variation in genomic experiments are batch effects—when samples are processed on different days, in different groups or by different people. However, there are also a large number of other variables that may have a major impact on high-throughput measurements. Here we describe the sva package for identifying, estimating and removing unwanted sources of variation in high-throughput experiments. The sva package supports surrogate variable estimation with the sva function, direct adjustment for known batch effects with the ComBat function and adjustment for batch and latent variables in prediction problems with the fsva function. Availability: The R package sva is freely available from http://www.bioconductor.org . Contact: jleek@jhsph.edu Supplementary information: Supplementary data are available at Bioinformatics online.
    Print ISSN: 1367-4803
    Electronic ISSN: 1460-2059
    Topics: Biology , Computer Science , Medicine
    Published by Oxford University Press
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  • 8
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    Pharmaco-miR: linking microRNAs and drug effects (2014)
    Oxford University Press
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    Publication Date: 2014-07-19
    Description: MicroRNAs (miRNAs) are short regulatory RNAs that down-regulate gene expression. They are essential for cell homeostasis and active in many disease states. A major discovery is the ability of miRNAs to determine the efficacy of drugs, which has given rise to the field of ‘miRNA pharmacogenomics’ through ‘Pharmaco-miRs’. miRNAs play a significant role in pharmacogenomics by down-regulating genes that are important for drug function. These interactions can be described as triplet sets consisting of a miRNA, a target gene and a drug associated with the gene. We have developed a web server which links miRNA expression and drug function by combining data on miRNA targeting and protein–drug interactions. miRNA targeting information derive from both experimental data and computational predictions, and protein–drug interactions are annotated by the Pharmacogenomics Knowledge base (PharmGKB). Pharmaco-miR’s input consists of miRNAs, genes and/or drug names and the output consists of miRNA pharmacogenomic sets or a list of unique associated miRNAs, genes and drugs. We have furthermore built a database, named Pharmaco-miR Verified Sets (VerSe), which contains miRNA pharmacogenomic data manually curated from the literature, can be searched and downloaded via Pharmaco-miR and informs on trends and generalities published in the field. Overall, we present examples of how Pharmaco-miR provides possible explanations for previously published observations, including how the cisplatin and 5-fluorouracil resistance induced by miR-148a may be caused by miR-148a targeting of the gene KIT. The information is available at www.Pharmaco-miR.org .
    Print ISSN: 1467-5463
    Electronic ISSN: 1477-4054
    Topics: Biology , Computer Science
    Published by Oxford University Press
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  • 9
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    Ionized gas discs in elliptical and S0 galaxies at z 〈 1 (2014)
    Oxford University Press
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    Publication Date: 2014-04-19
    Description: We analyse the extended, ionized-gas emission of 24 early-type galaxies (ETGs) at 0 〈  z  〈 1 from the ESO Distant Cluster Survey (EDisCS). We discuss different possible sources of ionization and favour star formation as the main cause of the observed emission. 10 galaxies have disturbed gas kinematics, while 14 have rotating gas discs. In addition, 15 galaxies are in the field, while 9 are in the infall regions of clusters. This implies that, if the gas has an internal origin, this is likely stripped as the galaxies get closer to the cluster centre. If the gas instead comes from an external source, then our results suggest that this is more likely acquired outside the cluster environment, where galaxy–galaxy interactions more commonly take place. We analyse the Tully–Fisher relation of the ETGs with gas discs, and compare them to EDisCS spirals. Taking a matched range of redshifts, M B  〈 –20, and excluding galaxies with large velocity uncertainties, we find that, at fixed rotational velocity, ETGs are 1.7 mag fainter in M B than spirals. At fixed stellar mass, we also find that ETGs have systematically lower specific star formation rates than spirals. This study constitutes an important step forward towards the understanding of the evolution of the complex ISM in ETGs by significantly extending the look-back-time baseline explored so far.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 10
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    BUDHIES I: characterizing the environments in and around two clusters at zbsime0.2 (2013)
    Oxford University Press
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    Publication Date: 2013-04-26
    Description: We present the optical spectroscopy for the Blind Ultra Deep H i Environmental Survey (BUDHIES). With the Westerbork Synthesis Radio Telescope, BUDHIES has detected H i in over 150 galaxies in and around two Abell clusters at z ~= 0.2. With the aim of characterizing the environments of the H i -detected galaxies, we obtained multifibre spectroscopy with the William Herschel Telescope. In this paper, we describe the spectroscopic observations, report redshifts and EW[O ii ] measurements for ~600 galaxies, and perform an environmental analysis. In particular, we present cluster velocity dispersion measurements for five clusters and groups in the BUDHIES volume, as well as a detailed substructure analysis.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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