Genetic variation of a bacterial pathogen within individuals with cystic fibrosis provides a record of selective pressures

Advances in sequencing have enabled the identification of mutations acquired by bacterial pathogens during infection1-10. However, it remains unclear whether adaptive mutations fix in the population or lead to pathogen diversification within the patient11,12. Here, we study the genotypic diversity of Burkholderia dolosa within people with cystic fibrosis by re-sequencing individual colonies and whole populations from single sputum samples. Extensive intra-sample diversity reveals that mutations rarely fix within a patient's pathogen population—instead, diversifying lineages coexist for many years. When strong selection is acting on a gene, multiple adaptive mutations arise but neither sweeps to fixation, generating lasting allele diversity that provides a recorded signature of past selection. Genes involved in outer-membrane components, iron scavenging and antibiotic resistance all showed this signature of within-patient selection. These results offer a general and rapid approach for identifying selective pressures acting on a pathogen in individual patients based on single clinical samples

Delays in dwarf novae I: The case of SS Cygni

Using the disc instability model and a simple but physically reasonable model for the X-ray, extreme UV, UV and optical emission of dwarf novae we investigate the time lags observed between the rise to outburst at different wavelengths. We find that for ``normal'', i.e. fast-rise outbursts, there is good agreement between the model and observations provided that the disc is truncated at a few white dwarf radii in quiescence, and that the viscosity parameter alpha is ~0.02 in quiescence and ~0.1 in outburst. In particular, the increased X-ray flux between the optical and EUV rise and at the end of an outburst, is a natural outcome of the model. We cannot explain, however, the EUV delay observed in anomalous outbursts because the disc instability model in its standard alpha-prescription form is unable to produce such outbursts. We also find that the UV delay is, contrary to common belief, slightly longer for inside-out than for outside-in outbursts, and that it is not a good indicator of the outburst type.Comment: 14 pages, 9 figures, accepted for publication in A&

Opposite prognostic roles of HIF1alpha and HIF2alpha expressions in bone metastatic clear cell renal cell cancer

BACKGROUND: Prognostic markers of bone metastatic clear cell renal cell cancer (ccRCC) are poorly established. We tested prognostic value of HIF1alpha/HIF2alpha and their selected target genes in primary tumors and corresponding bone metastases. RESULTS: Expression of HIF2alpha was lower in mRCC both at mRNA and protein levels (p/mRNA/=0.011, p/protein/=0.001) while HIF1alpha was similar to nmRCC. At the protein level, CAIX, GAPDH and GLUT1 were increased in mRCC. In all primary RCCs, low HIF2alpha and high HIF1alpha as well as CAIX, GAPDH and GLUT1 expressions correlated with adverse prognosis, while VEGFR2 and EPOR gene expressions were associated with favorable prognosis. Multivariate analysis confirmed high HIF2alpha protein expression as an independent risk factor. Prognostic validation of HIFs, LDH, EPOR and VEGFR2 in RNA-Seq data confirmed higher HIF1alpha gene expression in primary RCC as an adverse (p=0.07), whereas higher HIF2alpha and VEGFR2 expressions as favorable prognostic factors. HIF1alpha/HIF2alpha-index (HIF-index) proved to be an independent prognostic factor in both the discovery and the TCGA cohort. PATIENTS AND METHODS: Expressions of HIF1alpha and HIF2alpha as well as their 7 target genes were analysed on the mRNA and protein level in 59 non-metastatic ccRCCs (nmRCC), 40 bone metastatic primary ccRCCs (mRCC) and 55 corresponding bone metastases. Results were validated in 399 ccRCCs from the TCGA project. CONCLUSIONS: We identified HIF2alpha protein as an independent marker of the metastatic potential of ccRCC, however, unlike HIF1alpha, increased HIF2alpha expression is a favorable prognostic factor. The HIF-index incorporated these two markers into a strong prognostic biomarker of ccRCC

Functional Network Dynamics of the Language System

During linguistic processing, a set of brain regions on the lateral surfaces of the left frontal, temporal, and parietal cortices exhibit robust responses. These areas display highly correlated activity while a subject rests or performs a naturalistic language comprehension task, suggesting that they form an integrated functional system. Evidence suggests that this system is spatially and functionally distinct from other systems that support high-level cognition in humans. Yet, how different regions within this system might be recruited dynamically during task performance is not well understood. Here we use network methods, applied to fMRI data collected from 22 human subjects performing a language comprehension task, to reveal the dynamic nature of the language system. We observe the presence of a stable core of brain regions, predominantly located in the left hemisphere, that consistently coactivate with one another. We also observe the presence of a more flexible periphery of brain regions, predominantly located in the right hemisphere, that coactivate with different regions at different times. However, the language functional ROIs in the angular gyrus and the anterior temporal lobe were notable exceptions to this trend. By highlighting the temporal dimension of language processing, these results suggest a trade-off between a region's specialization and its capacity for flexible network reconfiguration

Trace Formulae and Spectral Statistics for Discrete Laplacians on Regular Graphs (I)

Trace formulae for d-regular graphs are derived and used to express the spectral density in terms of the periodic walks on the graphs under consideration. The trace formulae depend on a parameter w which can be tuned continuously to assign different weights to different periodic orbit contributions. At the special value w=1, the only periodic orbits which contribute are the non back- scattering orbits, and the smooth part in the trace formula coincides with the Kesten-McKay expression. As w deviates from unity, non vanishing weights are assigned to the periodic walks with back-scatter, and the smooth part is modified in a consistent way. The trace formulae presented here are the tools to be used in the second paper in this sequence, for showing the connection between the spectral properties of d-regular graphs and the theory of random matrices.Comment: 22 pages, 3 figure

A map of cell type-specific auxin responses

In plants, changes in local auxin concentrations can trigger a range of developmental processes as distinct tissues respond differently to the same auxin stimulus. However, little is known about how auxin is interpreted by individual cell types. We performed a transcriptomic analysis of responses to auxin within four distinct tissues of the Arabidopsis thaliana root and demonstrate that different cell types show competence for discrete responses. The majority of auxin-responsive genes displayed a spatial bias in their induction or repression. The novel data set was used to examine how auxin influences tissue-specific transcriptional regulation of cell-identity markers. Additionally, the data were used in combination with spatial expression maps of the root to plot a transcriptomic auxin-response gradient across the apical and basal meristem. The readout revealed a strong correlation for thousands of genes between the relative response to auxin and expression along the longitudinal axis of the root. This data set and comparative analysis provide a transcriptome-level spatial breakdown of the response to auxin within an organ where this hormone mediates many aspects of development

Bailout Embeddings and Neutrally Buoyant Particles in Three-Dimensional Flows

We use the bailout embeddings of three-dimensional volume-preserving maps to study qualitatively the dy- namics of small spherical neutrally buoyant impurities suspended in a time-periodic incompressible fluid flow. The accumulation of impurities in tubular vortical structures, the detachment of particles from fluid trajectories near hyperbolic invariant lines, and the formation of nontrivial three-dimensional structures in the distribution of particles are predicted.Comment: 4 pages, 3 figure