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The evolution of galaxies is connected to the growth of supermassive black holes in their centers. During the quasar phase, a huge luminosity is released as matter falls onto the black hole, and radiation-driven winds can transfer most of this energy back to the host galaxy. Over five different epochs, we detected the signatures of a nearly spherical stream of highly ionized gas in the broadband x-ray spectra of the luminous quasar PDS 456. This persistent wind is expelled at relativistic speeds from the inner accretion disk, and its wide aperture suggests an effective coupling with the ambient gas. The outflow's kinetic power larger than 1046 ergs per second is enough to provide the feedback required by models of black hole and host galaxy coevolution.

Background: Human papillomavirus (HPV)-positive oropharyngeal cancer (OPSCC) is associated with improved survival compared with HPV-negative disease. However, a minority of HPV-positive patients have poor prognosis. Currently, there is no generally accepted strategy for identifying these patients. Methods: We retrospectively analysed 270 consecutively treated OPSCC patients from three centres for effects of clinical, pathological, immunological, and molecular features on disease mortality. We used Cox regression to examine associations between factors and OPSCC death, and developed a prognostic model for 3-year mortality using logistic regression analysis. Results: Patients with HPV-positive tumours showed improved survival (hazard ratio (HR), 0.33 (0.21–0.53)). High levels of tumour-infiltrating lymphocytes (TILs) stratified HPV-positive patients into high-risk and low-risk groups (3-year survival; HPV-positive/TIL high =96%, HPV-positive/TIL low =59%). Survival of HPV-positive/TIL low patients did not differ from HPV-negative patients (HR, 1.01; P =0.98). We developed a prognostic model for HPV-positive tumours using a ‘training’ cohort from one centre; the combination of TIL levels, heavy smoking, and T-stage were significant (AUROC=0·87). This model was validated on patients from the other centres (detection rate 67%; false-positive rate 5.6%; AUROC=0·82). Interpretation: Our data suggest that an immune response, reflected by TIL levels in the primary tumour, has an important role in the improved survival seen in most HPV-positive patients, and is relevant for the clinical evaluation of HPV-positive OPSCC.

Land-use change is predicted to act as a driver of zoonotic disease emergence through human exposure to novel microbial diversity, but evidence for the effects of environmental change on microbial communities in vertebrates is lacking. We sample wild birds at 99 wildlife-livestock-human interfaces across Nairobi, Kenya, and use whole genome sequencing to characterise bacterial genes known to be carried on mobile genetic elements (MGEs) within avian-borne Escherichia coli ( n  = 241). By modelling the diversity of bacterial genes encoding virulence and antimicrobial resistance (AMR) against ecological and anthropogenic forms of urban environmental change, we demonstrate that communities of avian-borne bacterial genes are shaped by the assemblage of co-existing avian, livestock and human communities, and the habitat within which they exist. In showing that non-random processes structure bacterial genetic communities in urban wildlife, these findings suggest that it should be possible to forecast the effects of urban land-use change on microbial diversity. Disease transmission is particularly complex at the human-livestock-wildlife interface. Here the authors sample E. coli from wild birds near households in Nairobi and show that antimicrobial resistance gene diversity is correlated with human and lifestock density, while virulence gene diversity is correlated with avian species richness.

Background Transient ischemic attack (TIA) patients are at high risk of recurrent vascular events; timely management can reduce that risk by 70%. The Protocol-guided Rapid Evaluation of Veterans Experiencing New Transient Neurological Symptoms (PREVENT) developed, implemented, and evaluated a TIA quality improvement (QI) intervention aligned with Learning Healthcare System principles. Methods This stepped-wedge trial developed, implemented and evaluated a provider-facing, multi-component intervention to improve TIA care at six facilities. The unit of analysis was the medical center. The intervention was developed based on benchmarking data, staff interviews, literature, and electronic quality measures and included: performance data, clinical protocols, professional education, electronic health record tools, and QI support. The effectiveness outcome was the without-fail rate: the proportion of patients who receive all processes of care for which they are eligible among seven processes. The implementation outcomes were the number of implementation activities completed and final team organization level. The intervention effects on the without-fail rate were analyzed using generalized mixed-effects models with multilevel hierarchical random effects. Mixed methods were used to assess implementation, user satisfaction, and sustainability. Discussion PREVENT advanced three aspects of a Learning Healthcare System. Learning from Data: teams examined and interacted with their performance data to explore hypotheses, plan QI activities, and evaluate change over time. Learning from Each Other: Teams participated in monthly virtual collaborative calls. Sharing Best Practices: Teams shared tools and best practices. The approach used to design and implement PREVENT may be generalizable to other clinical conditions where time-sensitive care spans clinical settings and medical disciplines. Trial registration clinicaltrials.gov : NCT02769338 [May 11, 2016].

We report a previously undescribed bacterial behavior termed electrokinesis. This behavior was initially observed as a dramatic increase in cell swimming speed during reduction of solid MnO₂ particles by the dissimilatory metal-reducing bacterium Shewanella oneidensis MR-1. The same behavioral response was observed when cells were exposed to small positive applied potentials at the working electrode of a microelectrochemical cell and could be tuned by adjusting the potential on the working electrode. Electrokinesis was found to be different from both chemotaxis and galvanotaxis but was absent in mutants defective in electron transport to solid metal oxides. Using in situ video microscopy and cell tracking algorithms, we have quantified the response for different strains of Shewanella and shown that the response correlates with current-generating capacity in microbial fuel cells. The electrokinetic response was only exhibited by a subpopulation of cells closest to the MnO₂ particles or electrodes. In contrast, the addition of 1 mM 9,10-anthraquinone-2,6-disulfonic acid, a soluble electron shuttle, led to increases in motility in the entire population. Electrokinesis is defined as a behavioral response that requires functional extracellular electron transport and that is observed as an increase in cell swimming speeds and lengthened paths of motion that occur in the proximity of a redox active mineral surface or the working electrode of an electrochemical cell.

The dynamics and stability of multispot patterns to the Gray-Scott (GS) reaction-diffusion model in a two-dimensional domain is studied in the singularly perturbed limit of small diffusivity ... of one of the two solution components. A hybrid asymptotic-numerical approach based on combining the method of matched asymptotic expansions with the detailed numerical study of certain eigenvalue problems is used to predict the dynamical behavior and instability mechanisms of multispot quasi-equilibrium patterns for the GS model in the limit ... ... 0. From a numerical computation of the spectrum of these eigenvalue problems, phase diagrams in the GS parameter space corresponding to the onset of spot instabilities are obtained for various simple spatial configurations of multispot patterns. In addition, it is shown that there is a wide parameter range where a spot instability can be triggered only as a result of the intrinsic slow motion of the collection of spots. (ProQuest: ... denotes formulae/symbols omitted.)

With increasing interest in the diverse properties of organic acids and their application in synthetic pathways, developing biological tools for producing known and novel organic acids would be very valuable. In such a system, organic acids may be activated as coenzyme A (CoA) esters, then modified by CoA-dependent enzymes, followed by CoA liberation by a broad-acting thioesterase. This study has focused on the identification of suitable thioesterases (TE) for utilisation in such a pathway. Four recombinant hotdog-fold TEs were screened with a range of CoA esters in order to identify a highly active, broad spectrum TE. The TesB-like TE, RpaL, from Rhodopseudomonas palustris was found to be able to use aromatic, alicyclic and both long and short aliphatic CoA esters. Size exclusion chromatography, revealed RpaL to be a monomer of fused hotdog domains, in contrast to the complex quaternary structures found with similar TesB-like TEs. Nonetheless, sequence alignments showed a conserved catalytic triad despite the variation in quaternary arrangement. Kinetic analysis revealed a preference towards short-branched chain CoA esters with the highest specificity towards DL-β-hydroxybutyryl CoA (1.6 × 104 M−1 s−1), which was found to decrease as the acyl chain became longer and more functionalised. Substrate inhibition was observed with the fatty acyl n-heptadecanoyl CoA at concentrations exceeding 0.3 mM; however, this was attributed to its micellar aggregation properties. As a result of the broad activity observed with RpaL, it is a strong candidate for implementation in CoA ester pathways to generate modified or novel organic acids.

The existence, stability, and dynamics of localized patterns of criminal activity are studied for the reaction–diffusion model of urban crime introduced by Short et al. (Math. Models. Meth. Appl. Sci.18(Suppl.), (2008), 1249–1267). In the singularly perturbed limit of small diffusivity ratio, this model admits hotspot patterns, where criminal activity of high amplitude is localized within certain narrow spatial regions. By using a combination of asymptotic analysis and numerical path-following methods, hotspot equilibria are constructed on a finite 1-D domain and their bifurcation properties analysed as the diffusivity of criminals is varied. It is shown, both analytically and numerically, that new hotspots of criminal activity can be nucleated in low-crime regions with inconspicuous crime activity gradient when the spatial extent of these regions exceeds a critical threshold. These nucleations are referred to as “peak insertion” events, and for the steady-state problem, they occur near a saddle-node bifurcation point characterizing hotspot equilibria. For the time-dependent problem, a differential algebraic (DAE) system characterizing the slow dynamics of a collection of hotspots is derived, and the results compared favourably with full numerical simulations of the PDE system. The asymptotic theory to construct hotspot equilibria, and to derive the differential algebraic system for quasi-steady patterns, is based on the resolution of a triple-deck structure near the core of each hotspot and the identification of so-called switchback terms.

In the singularly perturbed limit of an asymptotically small diffusivity ratio ${\\varepsilon}^2$, the existence and stability of localized quasi-equilibrium multispot patterns is analyzed for the Brusselator reaction-diffusion model on the unit sphere. Formal asymptotic methods are used to derive a nonlinear algebraic system that characterizes quasi-equilibrium spot patterns and to formulate eigenvalue problems governing the stability of spot patterns to three types of \"fast\" ${\\mathcal O}(1)$ time-scale instabilities: self-replication, competition, and oscillatory instabilities of the spot amplitudes. The nonlinear algebraic system and the spectral problems are then studied using simple numerical methods, with emphasis on the special case where the spots have a common amplitude. Overall, the theoretical framework provides a hybrid asymptotic-numerical characterization of the existence and stability of spot patterns that is asymptotically correct to within all logarithmic correction terms in powers of $\\nu={-1/\\log{\\varepsilon}}$. From a leading-order-in-$\\nu$ analysis, and with an asymptotically large inhibitor diffusivity, some rigorous results for competition and oscillatory instabilities are obtained from an analysis of a new class of nonlocal eigenvalue problem (NLEP). Theoretical results for the stability of spot patterns are confirmed with full numerical computations of the Brusselator PDE system on the sphere using the closest point method. [PUBLICATION ABSTRACT]

Uptake and translocation of cationic nutrients play essential roles in physiological processes including plant growth, nutrition, signal transduction, and development. Approximately 5% of the Arabidopsis genome appears to encode membrane transport proteins. These proteins are classified in 46 unique families containing approximately 880 members. In addition, several hundred putative transporters have not yet been assigned to families. In this paper, we have analyzed the phylogenetic relationships of over 150 cation transport proteins. This analysis has focused on cation transporter gene families for which initial characterizations have been achieved for individual members, including potassium transporters and channels, sodium transporters, calcium antiporters, cyclic nucleotide-gated channels, cation diffusion facilitator proteins, natural resistance-associated macrophage proteins (NRAMP), and Zn-regulated transporter Fe-regulated transporter-like proteins. Phylogenetic trees of each family define the evolutionary relationships of the members to each other. These families contain numerous members, indicating diverse functions in vivo. Closely related isoforms and separate subfamilies exist within many of these gene families, indicating possible redundancies and specialized functions. To facilitate their further study, the PlantsT database (http://plantst.sdsc.edu) has been created that includes alignments of the analyzed cation transporters and their chromosomal locations.