Use of whole genome sequencing to estimate the mutation rate of Mycobacterium tuberculosis during latent infection

Tuberculosis poses a global health emergency, which has been compounded by the emergence of drug-resistant Mycobacterium tuberculosis (Mtb) strains. We used whole-genome sequencing to compare the accumulation of mutations in Mtb isolated from cynomolgus macaques with active, latent or reactivated disease. We sequenced 33 Mtb isolates from nine macaques with an average genome coverage of 93% and an average read depth of 117×. Based on the distribution of SNPs observed, we calculated the mutation rates for these disease states. We found a similar mutation rate during latency as during active disease or in a logarithmically growing culture over the same period of time. The pattern of polymorphisms suggests that the mutational burden in vivo is because of oxidative DNA damage. We show that Mtb continues to acquire mutations during disease latency, which may explain why isoniazid monotherapy for latent tuberculosis is a risk factor for the emergence of isoniazid resistance.     

Systemic methods for the analysis of failure

For more than 20 years systems-related ideas have been used to analyze and model failures and disasters of various sorts. The authors outline some examples of the links that have been forged between failures and systems over this period. An overview of the origins and development of systems failures teaching and research at the United Kingdom Open University is also presented, together with two systemic methodologies for the analysis of failure that have stemmed from this work. The implications of recent research on the application of the more sophisticated of these two methodologies are also discussed.     

Magnetic enhancement of superconductivity from electron spin domains

Since the discovery of superconductivity, there has been a drive to understand the mechanisms by which it occurs. The BCS (Bardeen-Cooper-Schrieffer) model successfully treats the electrons in conventional superconductors as pairs coupled by phonons (vibrational modes of oscillation) moving through the material, but there is as yet no accepted model for high-transition-temperature, organic or 'heavy fermion' superconductivity. Experiments that reveal unusual properties of those superconductors could therefore point the way to a deeper understanding of the underlying physics. In particular, the response of a material to a magnetic field can be revealing, because this usually reduces or quenches superconductivity. Here we report measurements of the heat capacity and magnetization that show that, for particular orientations of an external magnetic field, superconductivity in the heavy-fermion material CeCoIn(5) is enhanced through the magnetic moments (spins) of individual electrons. This enhancement occurs by fundamentally altering how the superconducting state forms, resulting in regions of superconductivity alternating with walls of spin-polarized unpaired electrons; this configuration lowers the free energy and allows superconductivity to remain stable. The large magnetic susceptibility of this material leads to an unusually strong coupling of the field to the electron spins, which dominates over the coupling to the electron orbits.     

Turning Hindsight into Foresight—Our Search for the “Philosopher's Stone” of Failure

This paper tells the story of work using Systems thinking to study failure. It describes the methodological developments that have taken place in this area at the Open University and looks at how the emphasis has shifted from the examination of past failures to the prediction and prevention of future failures and the facilitation of organizational learning through the analysis of failures. It ends with an outline of some of the work on systems failures that is currently under way.     

Effect of thiourea treatment on temperature selection and swimming behaviour inPhoxinus phoxinus

Résumé Le traitement par le thiourée a augmenté la mobilité chezPhoxinus phoxinus aux basses températures, mais non aux hautes températures. Les cas témoins ont évité les hautes températures; ce qui n'était pas le cas chez les poissons soumis à l'expérience. Ces faits suggèrent une corrélation entre le nouveau comportement et la glande thyroïde.