Cytological and transcript analyses reveal fat and lazy persister-like bacilli in tuberculous sputum

As nonreplicating tubercle bacilli are tolerant to the cidal action of antibiotics and resistant to multiple stresses, identification of this persister-like population of tubercle bacilli in sputum presents exciting and tractable new opportunities to investigate both responses to chemotherapy and the transmission of tuberculosis

A novel strategy for the identification of genomic islands by comparative analysis of the contents and contexts of tRNA sites in closely related bacteria

We devised software tools to systematically investigate the contents and contexts of bacterial tRNA and tmRNA genes, which are known insertion hotspots for genomic islands (GIs). The strategy, based on MAUVE-facilitated multigenome comparisons, was used to examine 87 Escherichia coli MG1655 tRNA and tmRNA genes and their orthologues in E.coli EDL933, E.coli CFT073 and Shigella flexneri Sf301. Our approach identified 49 GIs occupying ∼1.7 Mb that mapped to 18 tRNA genes, missing 2 but identifying a further 30 GIs as compared with Islander [Y. Mantri and K. P. Williams (2004), Nucleic Acids Res., 32, D55–D58]. All these GIs had many strain-specific CDS, anomalous GC contents and/or significant dinucleotide biases, consistent with foreign origins. Our analysis demonstrated marked conservation of sequences flanking both empty tRNA sites and tRNA-associated GIs across all four genomes. Remarkably, there were only 2 upstream and 5 downstream deletions adjacent to the 328 loci investigated. In silico PCR analysis based on conserved flanking regions was also used to interrogate hotspots in another eight completely or partially sequenced E.coli and Shigella genomes. The tools developed are ideal for the analysis of other bacterial species and will lead to in silico and experimental discovery of new genomic islands

Integrating Machine Learning for Planetary Science: Perspectives for the Next Decade

Machine learning (ML) methods can expand our ability to construct, and draw insight from large datasets. Despite the increasing volume of planetary observations, our field has seen few applications of ML in comparison to other sciences. To support these methods, we propose ten recommendations for bolstering a data-rich future in planetary science.Comment: 10 pages (expanded citations compared to 8 page submitted version for decadal survey), 3 figures, white paper submitted to the Planetary Science and Astrobiology Decadal Survey 2023-203

Michael Gove’s war on professional historical expertise : conservative curriculum reform, extreme Whig history and the place of imperial heroes in modern multicultural Britain

Six years of continuously baiting his opponents within the history profession eventually amounted to little where it mattered most. UK Secretary of State for Education, Michael Gove, finally backtracked in 2013 on his plans to impose a curriculum for English schools based on a linear chronology of the achievements of British national heroes. His ‘history as celebration’ curriculum was designed to instil pride amongst students in a supposedly shared national past, but would merely have accentuated how many students in modern multicultural Britain fail to recognise themselves in what is taught in school history lessons. Now that the dust has settled on Gove’s tenure as Secretary of State, the time is right for retrospective analysis of how his plans for the history curriculum made it quite so far. How did he construct an ‘ideological’ conception of expertise which allowed him to go toe-to-toe for so long with the ‘professional’ expertise of academic historians and history teachers? What does the content of this ideological expertise tell us about the politics of race within Conservative Party curriculum reforms? This article answers these questions to characterise Gove as a ‘whig historian’ of a wilfully extreme nature in his attachment to imperial heroes as the best way to teach national history in modern multicultural Britain

New Constraints on ΩM, ΩΛ, and w from an Independent Set of 11 High-Redshift Supernovae Observed with the Hubble Space Telescope

36 pags., 13 figs., 31 tabs., 1 app.We report measurements of ΩM, ΩΛ w from 11 supernovae (SNe) at z ¼ 0:36 0:86 with high-quality light curves measured using WFPC2 on the Hubble Space Telescope (HST). This is an independent set of high-redshift SNe that confirms previous SN evidence for an accelerating universe. The high-quality light curves available from photometry on WFPC2 make it possible for these 11 SNe alone to provide measurements of the cosmological parameters comparable in statistical weight to the previous results. Combined with earlier Supernova Cosmology Project data, the new SNe yield a measurement of the mass density ΩM ¼ 0:25þ0:07 Ω0:06 ðstatisticalÞ Λ 0:04 (identified systematics), or equivalently, a cosmological constant of ΩΛ ¼ 0:75þ0:06 Ω0:07 ðstatisticalÞ Λ 0:04 (identified systematics), under the assumptions of a flat universe and that the dark energy equation-of-state parameter has a constant value w ¼ Ω1.When the SN results are combined with independent flat-universe measurements of ΩM from cosmic microwave background and galaxy redshift distortion data, they provide a measurement of w ¼ Ω1:05þ0:15 Ω0:20 ðstatisticalÞ Λ 0:09 (identified systematic), if w is assumed to be constant in time. In addition to high-precision light-curve measurements, the new data offer greatly improved color measurements of the high-redshift SNe and hence improved host galaxy extinction estimates. These extinction measurements show no anomalous negative E(BΩ) at high redshift. The precision of the measurements is such that it is possible to perform a host galaxy extinction correction directly for individual SNe without any assumptions or priors on the parent E(BΩV) distribution. Our cosmological fits using full extinction corrections confirm that dark energy is required with PðΩΛ > 0Þ > 0:99, a result consistent with previous and current SN analyses that rely on the identification of a low-extinction subset or prior assumptions concerning the intrinsic extinction distribution.Support for this work was provided by NASA through grants HST-GO-07336.01-A and HST-GO-08346.01-A from the Space Telescope Science Institute, which is operated by the Association of Universities for Research in Astronomy, Inc., under NASA contract NAS 5-26555. This work was supported in part by the Director, Office of Science,Office of High Energy and Nuclear Physics, of the US Department of Energy under Contract DE-AC03- 76SF000098, by the Center for Particle Astrophysics, an NSF Science and Technology Center operated by the University of California, Berkeley, under Cooperative Agreement AST 91-20005. This work was supported in part by a NASA LTSA grant to P. E. N., G. A., S. P., and S. E. D., and W. M. W.-V. was supported in part by a National Science Foundation Graduate Research Fellowship. A.G. is a Royal Swedish Academy Research Fellow supported by a grant from the Knut and Alice Wallenberg Foundation.Peer Reviewe

New Constraints on ΩM\Omega_M, ΩΛ\Omega_\Lambda, and w from an Independent Set of Eleven High-Redshift Supernovae Observed with HST

We report measurements of $\Omega_M$, $\Omega_\Lambda$, and w from eleven supernovae at z=0.36-0.86 with high-quality lightcurves measured using WFPC-2 on the HST. This is an independent set of high-redshift supernovae that confirms previous supernova evidence for an accelerating Universe. Combined with earlier Supernova Cosmology Project data, the new supernovae yield a flat-universe measurement of the mass density $\Omega_M=0.25^{+0.07}_{-0.06}$ (statistical) $\pm0.04$ (identified systematics), or equivalently, a cosmological constant of $\Omega_\Lambda=0.75^{+0.06}_{-0.07}$ (statistical) $\pm0.04$ (identified systematics). When the supernova results are combined with independent flat-universe measurements of $\Omega_M$ from CMB and galaxy redshift distortion data, they provide a measurement of $w=-1.05^{+0.15}_{-0.20}$ (statistical) $\pm0.09$ (identified systematic), if w is assumed to be constant in time. The new data offer greatly improved color measurements of the high-redshift supernovae, and hence improved host-galaxy extinction estimates. These extinction measurements show no anomalous negative E(B-V) at high redshift. The precision of the measurements is such that it is possible to perform a host-galaxy extinction correction directly for individual supernovae without any assumptions or priors on the parent E(B-V) distribution. Our cosmological fits using full extinction corrections confirm that dark energy is required with $P(\Omega_\Lambda>0)>0.99$, a result consistent with previous and current supernova analyses which rely upon the identification of a low-extinction subset or prior assumptions concerning the intrinsic extinction distribution.Comment: Accepted for publication in Astrophysical Journal; For data tables and full-resolution figures, see http://supernova.lbl.go

Differential Producibility Analysis (DPA) of Transcriptomic Data with Metabolic Networks: Deconstructing the Metabolic Response of M. tuberculosis

A general paucity of knowledge about the metabolic state of Mycobacterium tuberculosis within the host environment is a major factor impeding development of novel drugs against tuberculosis. Current experimental methods do not allow direct determination of the global metabolic state of a bacterial pathogen in vivo, but the transcriptional activity of all encoded genes has been investigated in numerous microarray studies. We describe a novel algorithm, Differential Producibility Analysis (DPA) that uses a metabolic network to extract metabolic signals from transcriptome data. The method utilizes Flux Balance Analysis (FBA) to identify the set of genes that affect the ability to produce each metabolite in the network. Subsequently, Rank Product Analysis is used to identify those metabolites predicted to be most affected by a transcriptional signal. We first apply DPA to investigate the metabolic response of E. coli to both anaerobic growth and inactivation of the FNR global regulator. DPA successfully extracts metabolic signals that correspond to experimental data and provides novel metabolic insights. We next apply DPA to investigate the metabolic response of M. tuberculosis to the macrophage environment, human sputum and a range of in vitro environmental perturbations. The analysis revealed a previously unrecognized feature of the response of M. tuberculosis to the macrophage environment: a down-regulation of genes influencing metabolites in central metabolism and concomitant up-regulation of genes that influence synthesis of cell wall components and virulence factors. DPA suggests that a significant feature of the response of the tubercle bacillus to the intracellular environment is a channeling of resources towards remodeling of its cell envelope, possibly in preparation for attack by host defenses. DPA may be used to unravel the mechanisms of virulence and persistence of M. tuberculosis and other pathogens and may have general application for extracting metabolic signals from other “-omics” data

Soda and Tobacco Industry Corporate Social Responsibility Campaigns: How Do They Compare?

In an article that forms part of the PLoS Medicine series on Big Food, Andrew Cheyne and colleagues compare soda companies' corporate social responsibility (CSR) campaigns - which are designed to bolster the image and popularity of their products and to prevent regulation - with the tobacco industry's CSR campaigning

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons. A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology