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

Avoiding or restricting defectors in public goods games?

When creating a public good, strategies or mechanisms are required to handle defectors. We first show mathematically and numerically that prior agreements with posterior compensations provide a strategic solution that leads to substantial levels of cooperation in the context of public goods games, results that are corroborated by available experimental data. Notwithstanding this success, one cannot, as with other approaches, fully exclude the presence of defectors, raising the question of how they can be dealt with to avoid the demise of the common good. We show that both avoiding creation of the common good, whenever full agreement is not reached, and limiting the benefit that disagreeing defectors can acquire, using costly restriction mechanisms, are relevant choices. Nonetheless, restriction mechanisms are found the more favourable, especially in larger group interactions. Given decreasing restriction costs, introducing restraining measures to cope with public goods free-riding issues is the ultimate advantageous solution for all participants, rather than avoiding its creation.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

CWRML: representing crop wild relative conservation and use data in XML

Background Crop wild relatives are wild species that are closely related to crops. They are valuable as potential gene donors for crop improvement and may help to ensure food security for the future. However, they are becoming increasingly threatened in the wild and are inadequately conserved, both in situ and ex situ. Information about the conservation status and utilisation potential of crop wild relatives is diverse and dispersed, and no single agreed standard exists for representing such information; yet, this information is vital to ensure these species are effectively conserved and utilised. The European Community-funded project, European Crop Wild Relative Diversity Assessment and Conservation Forum, determined the minimum information requirements for the conservation and utilisation of crop wild relatives and created the Crop Wild Relative Information System, incorporating an eXtensible Markup Language (XML) schema to aid data sharing and exchange. Results Crop Wild Relative Markup Language (CWRML) was developed to represent the data necessary for crop wild relative conservation and ensure that they can be effectively utilised for crop improvement. The schema partitions data into taxon-, site-, and population-specific elements, to allow for integration with other more general conservation biology schemata which may emerge as accepted standards in the future. These elements are composed of sub-elements, which are structured in order to facilitate the use of the schema in a variety of crop wild relative conservation and use contexts. Pre-existing standards for data representation in conservation biology were reviewed and incorporated into the schema as restrictions on element data contents, where appropriate. Conclusion CWRML provides a flexible data communication format for representing in situ and ex situ conservation status of individual taxa as well as their utilisation potential. The development of the schema highlights a number of instances where additional standards-development may be valuable, particularly with regard to the representation of population-specific data and utilisation potential. As crop wild relatives are intrinsically no different to other wild plant species there is potential for the inclusion of CWRML data elements in the emerging standards for representation of biodiversity data

Metastatic colorectal cancer to a primary thyroid cancer

This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

La cuerda dulce – a tolerability and acceptability study of a novel approach to specimen collection for diagnosis of paediatric pulmonary tuberculosis

BACKGROUND: Recent data demonstrate the utility of the string test for the diagnosis of sputum-scarce HIV-associated TB in adults. We hypothesized that, if well-tolerated by children, this simple tool might offer a breakthrough in paediatric TB diagnosis. Thus the objective of this study, undertaken in the paediatric service of the Hospital Nacional Dos de Mayo, Lima, Perú, was to determine the tolerability and acceptability of the string test to paediatric TB suspects, their parents and nursing staff. METHODS: 22 paediatric subjects aged 3–14 years (median 8) under investigation for TB were invited to undergo 2 string tests (four-hour downtime each). Subjective and objective pain and discomfort rating scales were used to assess the perception of the subject, parent and attending nurse. RESULTS: Patients as young as 4 years tolerated the procedure extremely well with 84% willing to undergo a second procedure. Peak discomfort at the time of swallowing and of string retrieval was mild (30% of maximum possible score) and brief as judged by visual analogue ratings and objective indicators. Good concordance of parent/child and objective/subjective ratings strengthened the validity of these findings. CONCLUSION: The string test is well tolerated and achievable for most paediatric TB suspects as young as 4 years. A formal prospective paediatric efficacy study is now needed

Steady-state modulation of voltage-gated K+ channels in rat arterial smooth muscle by cyclic AMP-dependent protein kinase and protein phosphatase 2B

Voltage-gated potassium channels (Kv) are important regulators of membrane potential in vascular smooth muscle cells, which is integral to controlling intracellular Ca2+ concentration and regulating vascular tone. Previous work indicates that Kv channels can be modulated by receptor-driven alterations of cyclic AMP-dependent protein kinase (PKA) activity. Here, we demonstrate that Kv channel activity is maintained by tonic activity of PKA. Whole-cell recording was used to assess the effect of manipulating PKA signalling on Kv and ATP-dependent K+ channels of rat mesenteric artery smooth muscle cells. Application of PKA inhibitors, KT5720 or H89, caused a significant inhibition of Kv currents. Tonic PKA-mediated activation of Kv appears maximal as application of isoprenaline (a β-adrenoceptor agonist) or dibutyryl-cAMP failed to enhance Kv currents. We also show that this modulation of Kv by PKA can be reversed by protein phosphatase 2B/calcineurin (PP2B). PKA-dependent inhibition of Kv by KT5720 can be abrogated by pre-treatment with the PP2B inhibitor cyclosporin A, or inclusion of a PP2B auto-inhibitory peptide in the pipette solution. Finally, we demonstrate that tonic PKA-mediated modulation of Kv requires intact caveolae. Pre-treatment of the cells with methyl-β-cyclodextrin to deplete cellular cholesterol, or adding caveolin-scaffolding domain peptide to the pipette solution to disrupt caveolae-dependent signalling each attenuated PKA-mediated modulation of the Kv current. These findings highlight a novel, caveolae-dependent, tonic modulatory role of PKA on Kv channels providing new insight into mechanisms and the potential for pharmacological manipulation of vascular tone

Predicting mental imagery based BCI performance from personality, cognitive profile and neurophysiological patterns

Mental-Imagery based Brain-Computer Interfaces (MI-BCIs) allow their users to send commands to a computer using their brain-activity alone (typically measured by ElectroEncephaloGraphy— EEG), which is processed while they perform specific mental tasks. While very promising, MI-BCIs remain barely used outside laboratories because of the difficulty encountered by users to control them. Indeed, although some users obtain good control performances after training, a substantial proportion remains unable to reliably control an MI-BCI. This huge variability in user-performance led the community to look for predictors of MI-BCI control ability. However, these predictors were only explored for motor-imagery based BCIs, and mostly for a single training session per subject. In this study, 18 participants were instructed to learn to control an EEG-based MI-BCI by performing 3 MI-tasks, 2 of which were non-motor tasks, across 6 training sessions, on 6 different days. Relationships between the participants’ BCI control performances and their personality, cognitive profile and neurophysiological markers were explored. While no relevant relationships with neurophysiological markers were found, strong correlations between MI-BCI performances and mental-rotation scores (reflecting spatial abilities) were revealed. Also, a predictive model of MI-BCI performance based on psychometric questionnaire scores was proposed. A leave-one-subject-out cross validation process revealed the stability and reliability of this model: it enabled to predict participants’ performance with a mean error of less than 3 points. This study determined how users’ profiles impact their MI-BCI control ability and thus clears the way for designing novel MI-BCI training protocols, adapted to the profile of each user

Lack of Protection following Passive Transfer of Polyclonal Highly Functional Low-Dose Non-Neutralizing Antibodies

Recent immune correlates analysis from the RV144 vaccine trial has renewed interest in the role of non-neutralizing antibodies in mediating protection from infection. While neutralizing antibodies have proven difficult to induce through vaccination, extra-neutralizing antibodies, such as those that mediate antibody-dependent cellular cytotoxicity (ADCC), are associated with long-term control of infection. However, while several non-neutralizing monoclonal antibodies have been tested for their protective efficacy in vivo, no studies to date have tested the protective activity of naturally produced polyclonal antibodies from individuals harboring potent ADCC activity. Because ADCC-inducing antibodies are highly enriched in elite controllers (EC), we passively transferred highly functional non-neutralizing polyclonal antibodies, purified from an EC, to assess the potential impact of polyclonal non-neutralizing antibodies on a stringent SHIV-SF162P3 challenge in rhesus monkeys. Passive transfer of a low-dose of ADCC inducing antibodies did not protect from infection following SHIV-SF162P3 challenge. Passively administered antibody titers and gp120-specific, but not gp41-specific, ADCC and antibody induced phagocytosis (ADCP) were detected in the majority of the monkeys, but did not correlate with post infection viral control. Thus these data raise the possibility that gp120-specific ADCC activity alone may not be sufficient to control viremia post infection but that other specificities or Fc-effector profiles, alone or in combination, may have an impact on viral control and should be tested in future passive transfer experiments

Avian Use of Perennial Biomass Feedstocks as Post-Breeding and Migratory Stopover Habitat

Increased production of biomass crops in North America will require new agricultural land, intensify the cultivation of land already under production and introduce new types of biomass crops. Assessing the potential biodiversity impacts of novel agricultural systems is fundamental to the maintenance of biodiversity in agricultural landscapes, yet the consequences of expanded biomass production remain unclear. We evaluate the ability of two candidate second generation biomass feedstocks (switchgrass, Panicum virgatum, and mixed-grass prairie) not currently managed as crops to act as post-breeding and fall migratory stopover habitat for birds. In total, we detected 41 bird species, including grassland specialists and species of state and national conservation concern (e.g. Henslow's Sparrow, Ammodramus henslowii). Avian species richness was generally comparable in switchgrass and prairie and increased with patch size in both patch types. Grassland specialists were less abundant and less likely to occur in patches within highly forested landscapes and were more common and likely to occur in larger patches, indicating that this group is also area-sensitive outside of the breeding season. Variation in the biomass and richness of arthropod food within patches was generally unrelated to richness and abundance metrics. Total bird abundance and that of grassland specialists was higher in patches with greater vegetation structural heterogeneity. Collectively, we find that perennial biomass feedstocks have potential to provide post-breeding and migratory stopover habitat for birds, but that the placement and management of crops will be critical factors in determining their suitability for species of conservation concern. Industrialization of cellulosic bioenergy production that results in reduced crop structural heterogeneity is likely to dramatically reduce the suitability of perennial biomass crops for birds