Association between bacterial homoplastic variants and radiological pathology in tuberculosis.

Funder: Biotechnology and Biological Sciences Research Council; FundRef: http://dx.doi.org/10.13039/501100000268Funder: FP7 People: Marie-Curie Actions; FundRef: http://dx.doi.org/10.13039/100011264; Grant(s): EU FP7-PEOPLE-2013-IRSES - Marie Curie Action DEANBACKGROUND: Understanding how pathogen genetic factors contribute to pathology in TB could enable tailored treatments to the most pathogenic and infectious strains. New strategies are needed to control drug-resistant TB, which requires longer and costlier treatment. We hypothesised that the severity of radiological pathology on the chest radiograph in TB disease was associated with variants arising independently, multiple times (homoplasies) in the Mycobacterium tuberculosis genome. METHODS: We performed whole genome sequencing (Illumina HiSeq2000 platform) on M. tuberculosis isolates from 103 patients with drug-resistant TB in Lima between 2010 and 2013. Variables including age, sex, HIV status, previous TB disease and the percentage of lung involvement on the pretreatment chest radiograph were collected from health posts of the national TB programme. Genomic variants were identified using standard pipelines. RESULTS: Two mutations were significantly associated with more widespread radiological pathology in a multivariable regression model controlling for confounding variables (Rv2828c.141, RR 1.3, 95% CI 1.21 to 1.39, p<0.01; rpoC.1040 95% CI 1.77 to 2.16, RR 1.9, p<0.01). The rpoB.450 mutation was associated with less extensive radiological pathology (RR 0.81, 95% CI 0.69 to 0.94, p=0.03), suggestive of a bacterial fitness cost for this mutation in vivo. Patients with a previous episode of TB disease and those between 10 and 30 years of age also had significantly increased radiological pathology. CONCLUSIONS: This study is the first to compare the M. tuberculosis genome to radiological pathology on the chest radiograph. We identified two variants significantly positively associated with more widespread radiological pathology and one with reduced pathology. Prospective studies are warranted to determine whether mutations associated with increased pathology also predict the spread of drug-resistant TB

Genomic signatures of pre-resistance in Mycobacterium tuberculosis.

Recent advances in bacterial whole-genome sequencing have resulted in a comprehensive catalog of antibiotic resistance genomic signatures in Mycobacterium tuberculosis. With a view to pre-empt the emergence of resistance, we hypothesized that pre-existing polymorphisms in susceptible genotypes (pre-resistance mutations) could increase the risk of becoming resistant in the future. We sequenced whole genomes from 3135 isolates sampled over a 17-year period. After reconstructing ancestral genomes on time-calibrated phylogenetic trees, we developed and applied a genome-wide survival analysis to determine the hazard of resistance acquisition. We demonstrate that M. tuberculosis lineage 2 has a higher risk of acquiring resistance than lineage 4, and estimate a higher hazard of rifampicin resistance evolution following isoniazid mono-resistance. Furthermore, we describe loci and genomic polymorphisms associated with a higher risk of resistance acquisition. Identifying markers of future antibiotic resistance could enable targeted therapy to prevent resistance emergence in M. tuberculosis and other pathogens

Genetic diversity of sweet sorghum germplasm in Mexico using AFLP and SSR markers

O objetivo deste trabalho foi avaliar a diversidade e as relações genéticas entre linhagens e variedades de sorgo sacarino (Sorghum bicolor) do banco de germoplasma do Instituto Nacional de Investigações Florestais, Agrícolas e Pecuárias, México, por meio de marcadores AFLP e SSR. Os marcadores moleculares revelaram robustez dos perfis de amplificação e permitiram diferenciar os 41 genótipos de sorgo sacarino avaliados. A análise da frequência e da distribuição dos fragmentos polimórficos permitiu detectar alelos únicos (AFLP) e raros (SSR) em diversos genótipos (RBSS‑8, RBSS‑9, RBSS‑25, RBSS‑32 e RBSS‑37), o que indica que estes marcadores podem estar associados a uma característica que ainda não foi determinada ou podem ser úteis para a identificação destes genótipos. As relações genéticas indicaram a presença de pelo menos dois tipos de sorgo sacarino: um grupo de genótipos modernos usados para a produção de açúcar e biocombustíveis, e outro grupo formado por genótipos antigos e modernos utilizados para a produção de xaropes. Genótipos de sorgo sacarino podem ser usados para o desenvolvimento de novas variedades com maior conteúdo de açúcar e caldo.The objective of this work was to evaluate the diversity and genetic relationships between lines and varieties of the sweet sorghum (Sorghum bicolor) germplasm bank of the National Institute for Forestry, Agriculture and Livestock Research, Mexico, using AFLP and SSR markers. The molecular markers revealed robust amplification profiles and were able to differentiate the 41 genotypes of sweet sorghum evaluated. Analysis of the frequency and distribution of polymorphic fragments allowed for the detection of unique (AFLP) and rare (SSR) alleles in several genotypes (RBSS‑8, RBSS‑9, RBSS‑25, RBSS‑32, and RBSS‑37), indicating that these markers may be associated with a feature that has not yet been determined or may be useful for the identification of these genotypes. The genetic relationships indicated the presence of at least two types of sweet sorghum: a group of modern genotypes used for sugar and biofuel production, and another group consisting of historic and modern genotypes used for the production of syrups. Sweet sorghum genotypes may be used to develop new varieties with higher sugar and juice contents

Challenging a culture of racial equivalence

We live at a time when our understandings and conceptualizations of ‘racism’ are often highly imprecise, broad, and used to describe a wide range of racialized phenomena. In this article, I raise some important questions about how the term racism is used and understood in contemporary British society by drawing on some recent cases of alleged racism in football and politics, many of which have been played out via new media technologies. A broader understanding of racism, through the use of the term ‘racialization’, has been helpful in articulating a more nuanced and complex understanding of racial incidents, especially of people’s (often ambivalent) beliefs and behaviours. However, the growing emphasis upon ‘racialization’ has led to a conceptualization of racism which increasingly involves multiple perpetrators, victims, and practices without enough consideration of how and why particular interactions and practices constitute racism as such.The trend toward a growing culture of racial equivalence is worrying, as it denudes the idea of racism of its historical basis, severity and power.These frequent and commonplace assertions of racism in the public sphere paradoxically end up trivializing and homogenizing quite different forms of racialized interactions. I conclude that we need to retain the term ‘racism’, but we need to differentiate more clearly between ‘racism’ (as an historical and structured system of domination) from the broader notion of ‘racialization’

Low-Energy Physics in Neutrino LArTPCs

In this white paper, we outline some of the scientific opportunities and challenges related to detection and reconstruction of low-energy (less than 100 MeV) signatures in liquid argon time-projection chamber (LArTPC) detectors. Key takeaways are summarized as follows. 1) LArTPCs have unique sensitivity to a range of physics and astrophysics signatures via detection of event features at and below the few tens of MeV range. 2) Low-energy signatures are an integral part of GeV-scale accelerator neutrino interaction final states, and their reconstruction can enhance the oscillation physics sensitivities of LArTPC experiments. 3) BSM signals from accelerator and natural sources also generate diverse signatures in the low-energy range, and reconstruction of these signatures can increase the breadth of BSM scenarios accessible in LArTPC-based searches. 4) Neutrino interaction cross sections and other nuclear physics processes in argon relevant to sub-hundred-MeV LArTPC signatures are poorly understood. Improved theory and experimental measurements are needed. Pion decay-at-rest sources and charged particle and neutron test beams are ideal facilities for experimentally improving this understanding. 5) There are specific calibration needs in the low-energy range, as well as specific needs for control and understanding of radiological and cosmogenic backgrounds. 6) Novel ideas for future LArTPC technology that enhance low-energy capabilities should be explored. These include novel charge enhancement and readout systems, enhanced photon detection, low radioactivity argon, and xenon doping. 7) Low-energy signatures, whether steady-state or part of a supernova burst or larger GeV-scale event topology, have specific triggering, DAQ and reconstruction requirements that must be addressed outside the scope of conventional GeV-scale data collection and analysis pathways

Low exposure long-baseline neutrino oscillation sensitivity of the DUNE experiment

The Deep Underground Neutrino Experiment (DUNE) will produce world-leading neutrino oscillation measurements over the lifetime of the experiment. In this work, we explore DUNE's sensitivity to observe charge-parity violation (CPV) in the neutrino sector, and to resolve the mass ordering, for exposures of up to 100 kiloton-megawatt-years (kt-MW-yr). The analysis includes detailed uncertainties on the flux prediction, the neutrino interaction model, and detector effects. We demonstrate that DUNE will be able to unambiguously resolve the neutrino mass ordering at a 3$\sigma$ (5$\sigma$) level, with a 66 (100) kt-MW-yr far detector exposure, and has the ability to make strong statements at significantly shorter exposures depending on the true value of other oscillation parameters. We also show that DUNE has the potential to make a robust measurement of CPV at a 3$\sigma$ level with a 100 kt-MW-yr exposure for the maximally CP-violating values \delta_{\rm CP}} = \pm\pi/2. Additionally, the dependence of DUNE's sensitivity on the exposure taken in neutrino-enhanced and antineutrino-enhanced running is discussed. An equal fraction of exposure taken in each beam mode is found to be close to optimal when considered over the entire space of interest