Genomic Context of Azole Resistance Mutations in Aspergillus fumigatus Determined Using Whole-Genome Sequencing.

A rapid and global emergence of azole resistance has been observed in the pathogenic fungus Aspergillus fumigatus over the past decade. The dominant resistance mechanism appears to be of environmental origin and involves mutations in the cyp51A gene, which encodes a protein targeted by triazole antifungal drugs. Whole-genome sequencing (WGS) was performed for high-resolution single-nucleotide polymorphism (SNP) analysis of 24 A. fumigatus isolates, including azole-resistant and susceptible clinical and environmental strains obtained from India, the Netherlands, and the United Kingdom, in order to assess the utility of WGS for characterizing the alleles causing resistance. WGS analysis confirmed that TR34/L98H (a mutation comprising a tandem repeat [TR] of 34 bases in the promoter of the cyp51A gene and a leucine-to-histidine change at codon 98) is the sole mechanism of azole resistance among the isolates tested in this panel of isolates. We used population genomic analysis and showed that A. fumigatus was panmictic, with as much genetic diversity found within a country as is found between continents. A striking exception to this was shown in India, where isolates are highly related despite being isolated from both clinical and environmental sources across >1,000 km; this broad occurrence suggests a recent selective sweep of a highly fit genotype that is associated with the TR34/L98H allele. We found that these sequenced isolates are all recombining, showing that azole-resistant alleles are segregating into diverse genetic backgrounds. Our analysis delineates the fundamental population genetic parameters that are needed to enable the use of genome-wide association studies to identify the contribution of SNP diversity to the generation and spread of azole resistance in this medically important fungus. IMPORTANCE: Resistance to azoles in the ubiquitous ascomycete fungus A. fumigatus was first reported from clinical isolates collected in the United States during the late 1980s. Over the last decade, an increasing number of A. fumigatus isolates from the clinic and from nature have been found to show resistance to azoles, suggesting that resistance is emerging through selection by the widespread usage of agricultural azole antifungal compounds. Aspergillosis is an emerging clinical problem, with high rates of treatment failures necessitating the development of new techniques for surveillance and for determining the genome-wide basis of azole resistance in A. fumigatus

Fundamental properties of the Population II fiducial stars HD 122563 and Gmb 1830 from CHARA interferometric observations

We have determined the angular diameters of two metal-poor stars, HD 122563 and Gmb 1830, using CHARA and Palomar Testbed Interferometer observations. For the giant star HD 122563, we derive an angular diameter theta_3D = 0.940 +- 0.011 milliarcseconds (mas) using limb-darkening from 3D convection simulations and for the dwarf star Gmb 1830 (HD 103095) we obtain a 1D limb-darkened angular diameter theta_1D = 0.679 +- 0.007 mas. Coupling the angular diameters with photometry yields effective temperatures with precisions better than 55 K (Teff = 4598 +- 41 K and 4818 +- 54 K --- for the giant and the dwarf star, respectively). Including their distances results in very well-determined luminosities and radii (L = 230 +- 6 L_sun, R = 23.9 +- 1.9 R_sun and L = 0.213 +- 0.002 L_sun, R = 0.664 +- 0.015 R_sun, respectively). We used the CESAM2k stellar structure and evolution code in order to produce models that fit the observational data. We found values of the mixing-length parameter alpha (which describes 1D convection) that depend on the mass of the star. The masses were determined from the models with precisions of <3% and with the well-measured radii excellent constraints on the surface gravity are obtained (log g = 1.60 +- 0.04, 4.59 +- 0.02, respectively). The very small errors on both log g and Teff provide stringent constraints for spectroscopic analyses given the sensitivity of abundances to both of these values. The precise determination of Teff for the two stars brings into question the photometric scales for metal-poor stars.Comment: accepted A&A, 8 dbl-column pages, incl. 7 tables and 4 figure

Optical conversion of pure spin currents in hybrid molecular devices

Carbon-based molecules offer unparalleled potential for THz and optical devices controlled by pure spin currents: a low-dissipation flow of electronic spins with no net charge displacement. However, the research so far has been focused on the electrical conversion of the spin imbalance, where molecular materials are used to mimic their crystalline counterparts. Here, we use spin currents to access the molecular dynamics and optical properties of a fullerene layer. The spin mixing conductance across Py/C60 interfaces is increased by 10% (5 × 1018 m−2) under optical irradiation. Measurements show up to a 30% higher light absorbance and a factor of 2 larger photoemission during spin pumping. We also observe a 0.15 THz slowdown and a narrowing of the vibrational peaks. The effects are attributed to changes in the non-radiative damping and energy transfer. This opens new research paths in hybrid magneto-molecular optoelectronics, and the optical detection of spin physics in these materials

The politicisation of evaluation: constructing and contesting EU policy performance

Although systematic policy evaluation has been conducted for decades and has been growing strongly within the European Union (EU) institutions and in the member states, it remains largely underexplored in political science literatures. Extant work in political science and public policy typically focuses on elements such as agenda setting, policy shaping, decision making, or implementation rather than evaluation. Although individual pieces of research on evaluation in the EU have started to emerge, most often regarding policy “effectiveness” (one criterion among many in evaluation), a more structured approach is currently missing. This special issue aims to address this gap in political science by focusing on four key focal points: evaluation institutions (including rules and cultures), evaluation actors and interests (including competencies, power, roles and tasks), evaluation design (including research methods and theories, and their impact on policy design and legislation), and finally, evaluation purpose and use (including the relationships between discourse and scientific evidence, political attitudes and strategic use). The special issue considers how each of these elements contributes to an evolving governance system in the EU, where evaluation is playing an increasingly important role in decision making

Niche as a determinant of word fate in online groups

Patterns of word use both reflect and influence a myriad of human activities and interactions. Like other entities that are reproduced and evolve, words rise or decline depending upon a complex interplay between {their intrinsic properties and the environments in which they function}. Using Internet discussion communities as model systems, we define the concept of a word niche as the relationship between the word and the characteristic features of the environments in which it is used. We develop a method to quantify two important aspects of the size of the word niche: the range of individuals using the word and the range of topics it is used to discuss. Controlling for word frequency, we show that these aspects of the word niche are strong determinants of changes in word frequency. Previous studies have already indicated that word frequency itself is a correlate of word success at historical time scales. Our analysis of changes in word frequencies over time reveals that the relative sizes of word niches are far more important than word frequencies in the dynamics of the entire vocabulary at shorter time scales, as the language adapts to new concepts and social groupings. We also distinguish endogenous versus exogenous factors as additional contributors to the fates of words, and demonstrate the force of this distinction in the rise of novel words. Our results indicate that short-term nonstationarity in word statistics is strongly driven by individual proclivities, including inclinations to provide novel information and to project a distinctive social identity.Comment: Supporting Information is available here: http://www.plosone.org/article/fetchSingleRepresentation.action?uri=info:doi/10.1371/journal.pone.0019009.s00

Hybridization in parasites: consequences for adaptive evolution, pathogenesis and public health in a changing world

[No abstract available

Do adults with high functioning autism or Asperger Syndrome differ in empathy and emotion recognition?

The present study examined whether adults with high functioning autism (HFA) showed greater difficulties in (i) their self-reported ability to empathise with others and/or (ii) their ability to read mental states in others’ eyes than adults with Asperger syndrome (AS). The Empathy Quotient (EQ) and ‘Reading the Mind in the Eyes’ Test (Eyes Test) were compared in 43 adults with AS and 43 adults with HFA. No significant difference was observed on EQ score between groups, while adults with AS performed significantly better on the Eyes Test than those with HFA. This suggests that adults with HFA may need more support, particularly in mentalizing and complex emotion recognition, and raises questions about the existence of subgroups within autism spectrum conditions

Calcium Homeostasis in Myogenic Differentiation Factor 1 (MyoD)-Transformed, Virally-Transduced, Skin-Derived Equine Myotubes

Dysfunctional skeletal muscle calcium homeostasis plays a central role in the pathophysiology of several human and animal skeletal muscle disorders, in particular, genetic disorders associated with ryanodine receptor 1 (RYR1) mutations, such as malignant hyperthermia, central core disease, multiminicore disease and certain centronuclear myopathies. In addition, aberrant skeletal muscle calcium handling is believed to play a pivotal role in the highly prevalent disorder of Thoroughbred racehorses, known as Recurrent Exertional Rhabdomyolysis. Traditionally, such defects were studied in human and equine subjects by examining the contractile responses of biopsied muscle strips exposed to caffeine, a potent RYR1 agonist. However, this test is not widely available and, due to its invasive nature, is potentially less suitable for valuable animals in training or in the human paediatric setting. Furthermore, increasingly, RYR1 gene polymorphisms (of unknown pathogenicity and significance) are being identified through next generation sequencing projects. Consequently, we have investigated a less invasive test that can be used to study calcium homeostasis in cultured, skin-derived fibroblasts that are converted to the muscle lineage by viral transduction with a MyoD (myogenic differentiation 1) transgene. Similar models have been utilised to examine calcium homeostasis in human patient cells, however, to date, there has been no detailed assessment of the cells’ calcium homeostasis, and in particular, the responses to agonists and antagonists of RYR1. Here we describe experiments conducted to assess calcium handling of the cells and examine responses to treatment with dantrolene, a drug commonly used for prophylaxis of recurrent exertional rhabdomyolysis in horses and malignant hyperthermia in humans

Modelling the cost-effectiveness of public awareness campaigns for the early detection of non-small-cell lung cancer

Background: Survival rates in lung cancer in England are significantly lower than in many similar countries. A range of Be Clear on Cancer (BCOC) campaigns have been conducted targeting lung cancer and found to improve the proportion of diagnoses at the early stage of disease. This paper considers the cost-effectiveness of such campaigns, evaluating the effect of both the regional and national BCOC campaigns on the stage distribution of non-small-cell lung cancer (NSCLC) at diagnosis. Methods: A natural history model of NSCLC was developed using incidence data, data elicited from clinical experts and model calibration techniques. This structure is used to consider the lifetime cost and quality-adjusted survival implications of the early awareness campaigns. Incremental cost-effectiveness ratios (ICERs) in terms of additional costs per quality-adjusted life-years (QALYs) gained are presented. Two scenario analyses were conducted to investigate the role of changes in the ‘worried-well’ population and the route of diagnosis that might occur as a result of the campaigns. Results: The base-case theoretical model found the regional and national early awareness campaigns to be associated with QALY gains of 289 and 178 QALYs and ICERs of d13 660 and d18 173 per QALY gained, respectively. The scenarios found that increases in the ‘worried-well’ population may impact the cost-effectiveness conclusions. Conclusions: Subject to the available evidence, the analysis suggests that early awareness campaigns in lung cancer have the potential to be cost-effective. However, significant additional research is required to address many of the limitations of this study. In addition, the estimated natural history model presents previously unavailable estimates of the prevalence and rate of disease progression in the undiagnosed population