Anr and Its Activation by PlcH Activity in Pseudomonas aeruginosa Host Colonization and Virulence

Pseudomonas aeruginosa hemolytic phospholipase C (PlcH) degrades phosphatidylcholine (PC), an abundant lipid in cell membranes and lung surfactant. A ΔplcHR mutant, known to be defective in virulence in animal models, was less able to colonize epithelial cell monolayers and was defective in biofilm formation on plastic when grown in lung surfactant. Microarray analyses found that strains defective in PlcH production had lower levels of Anr-regulated transcripts than the wild type. PC degradation stimulated the Anr regulon in an Anr-dependent manner under conditions where Anr activity was submaximal because of the presence of oxygen. Two PC catabolites, choline and glycine betaine (GB), were sufficient to stimulate Anr activity, and their catabolism was required for Anr activation. The addition of choline or GB to glucose-containing medium did not alter Anr protein levels, growth rates, or respiratory activity, and Anr activation could not be attributed to the osmoprotectant functions of GB. The Δanr mutant was defective in virulence in a mouse pneumonia model. Several lines of evidence indicate that Anr is important for the colonization of biotic and abiotic surfaces in both P. aeruginosa PAO1 and PA14 and that increases in Anr activity resulted in enhanced biofilm formation. Our data suggest that PlcH activity promotes Anr activity in oxic environments and that Anr activity contributes to virulence, even in the acute infection phase, where low oxygen tensions are not expected. This finding highlights the relationships among in vivo bacterial metabolism, the activity of the oxygen-sensitive regulator Anr, and virulence

Developing a patient-centred tool for pain measurement and evaluation in autosomal dominant polycystic kidney disease.

BACKGROUND: Pain affects 60% of the autosomal dominant polycystic kidney disease (ADPKD) population. Despite being an early and debilitating symptom, it is poorly characterized and management is suboptimal. This study aimed to develop an ADPKD-specific pain assessment tool (APAT) to facilitate pain research. METHODS: Following a systematic review of PATs used in ADPKD studies and against international recommendations for pain trials, our multi-disciplinary team of clinical experts and patients constructed an ADPKD-pain conceptual framework of key pain evaluation themes. We compiled a new APAT covering domains prioritized within our framework using components of questionnaires validated in other chronic pain disorders. The APAT was administered longitudinally within a randomized high-water intake trial (NCT02933268) to ascertain feasibility and provide pilot data on ADPKD pain. RESULTS: Thirty-nine ADPKD participants with chronic kidney disease Stages 1-4 provided 129 APAT responses. Each participant completed a median of 3 (range 1-10) assessments. Respondents' mean ± standard deviation age was 47 ± 13 years; 59% (23) were female; and 69% (27) had enlarged kidneys with median time from diagnosis 14.2 (interquartile range 7.0-25.9) years. Pain (52%) and associated analgesic use (29%) were common. Pain severity was associated with increasing age [odds ratio (OR) = 1.07, P = 0.009], female gender (OR = 4.34, P = 0.018), estimated glomerular filtration rate <60 mL/min/1.73 m2 (OR = 5.45, P = 0.021) and hypertension (OR = 12.11, P = 0.007), but not with kidney size (P = 0.23). The APAT achieved good internal consistency (Cronbach's alpha coefficient = 0.91) and test-retest reliability (domain intra-class correlation coefficients ranging from 0.62 to 0.90). CONCLUSIONS: The APAT demonstrated good acceptability and reliability, and following further validation in a larger cohort could represent an invaluable tool for future ADPKD pain studies.Addenbrookes Charitable Trust Kidney Care UK British Renal Society Kidney Research U

A Strategy for Finding Near Earth Objects with the SDSS Telescope

We present a detailed observational strategy for finding Near Earth Objects (NEOs) with the Sloan Digital Sky Survey (SDSS) telescope. We investigate strategies in normal, unbinned mode as well as binning the CCDs 2x2 or 3x3, which affects the sky coverage rate and the limiting apparent magnitude. We present results from 1 month, 3 year and 10 year simulations of such surveys. For each cadence and binning mode, we evaluate the possibility of achieving the Spaceguard goal of detecting 90% of 1 km NEOs (absolute magnitude H <= 18 for an albedo of 0.1). We find that an unbinned survey is most effective at detecting H <= 20 NEOs in our sample. However, a 3x3 binned survey reaches the Spaceguard Goal after only seven years of operation. As the proposed large survey telescopes (PanStarss; LSST) are at least 5-10 years from operation, an SDSS NEO survey could make a significant contribution to the detection and photometric characterization of the NEO population.Comment: Accepted by AJ -- 12 pages, 11 figure

Imaging and Demography of the Host Galaxies of High-Redshift Type Ia Supernovae

We present the results of a study of the host galaxies of high redshift Type Ia supernovae (SNe Ia). We provide a catalog of 18 hosts of SNe Ia observed with the Hubble Space Telescope (HST) by the High-z Supernova Search Team (HZT), including images, scale-lengths, measurements of integrated (Hubble equivalent) BVRIZ photometry in bands where the galaxies are brighter than m ~ 25 mag, and galactocentric distances of the supernovae. We compare the residuals of SN Ia distance measurements from cosmological fits to measurable properties of the supernova host galaxies that might be expected to correlate with variable properties of the progenitor population, such as host galaxy color and position of the supernova. We find mostly null results; the current data are generally consistent with no correlations of the distance residuals with host galaxy properties in the redshift range 0.42 < z < 1.06. Although a subsample of SN hosts shows a formally significant (3-sigma) correlation between apparent V-R host color and distance residuals, the correlation is not consistent with the null results from other host colors probed by our largest samples. There is also evidence for the same correlations between SN Ia properties and host type at low redshift and high redshift. These similarities support the current practice of extrapolating properties of the nearby population to high redshifts pending more robust detections of any correlations between distance residuals from cosmological fits and host properties.Comment: 35 pages, 12 figures, 4 tables, accepted for publication in A

How Can Reasoner Performance of ABox Intensive Ontologies Be Predicted?

Reasoner performance prediction of ontologies in OWL 2 language has been studied so far from different dimensions. One key aspect of these studies has been the prediction of how much time a particular task for a given ontology will consume. Several approaches have adopted different machine learning techniques to predict time consumption of ontologies already. However, these studies focused on capturing general aspects of the ontologies (i.e., mainly the complexity of their TBoxes), while paying little attention to ABox intensive ontologies. To address this issue, in this paper, we propose to improve the representativeness of ontology metrics by developing new metrics which focus on the ABox features of ontologies. Our experiments show that the proposed metrics contribute to overall prediction accuracy for all ontologies in general without causing side-effects

Anharmonic Evolution of the Cosmic Axion Density Spectrum

We present analytic solutions to the spatially homogeneous axion field equation, using a model potential which strongly resembles the standard anharmonic $(1-\cos N\theta)$ potential, but contains only a piece-wise second order term. Our exactly soluble model for $\theta(t)$ spans the entire range $[-\pi/N,\pi/N]$. In particular, we are able to confirm (i) Turner's numeric correction factors \cite{Turner} to the adiabatic and harmonic analytic treatments of homogeneous axion oscillations, and (ii) Lyth's estimate \cite{Lyth} valid near the metastable misalignment angle $\pi/N$ at the peak of the potential. We compute the enhancement of axion density fluctuations that occurs when the axion mass becomes significant at $T\sim 1$ GeV. We find that the anharmonicity amplifies density \mbox{f}luctuations, but only significantly for relatively large initial misalignment angles. The enhancement factor is $\sim$ (2,3,4,13) for $\theta_{\rm in}\sim (0.85,0.90,0.95,0.99)\times\pi$.Comment: 26 pages, 6 figures appended as a ps-file, Latex, DAMTP-94-21, VAND-TH-94-

On globally static and stationary cosmologies with or without a cosmological constant and the Dark Energy problem

In the framework of spatially averaged inhomogeneous cosmologies in classical General Relativity, effective Einstein equations govern the regional and the global dynamics of averaged scalar variables of cosmological models. A particular solution may be characterized by a cosmic equation of state. In this paper it is pointed out that a globally static averaged dust model is conceivable without employing a compensating cosmological constant. Much in the spirit of Einstein's original model we discuss consequences for the global, but also for the regional properties of this cosmology. We then consider the wider class of globally stationary cosmologies that are conceivable in the presented framework. All these models are based on exact solutions of the averaged Einstein equations and provide examples of cosmologies in an out-of-equilibrium state, which we characterize by an information-theoretical measure. It is shown that such cosmologies preserve high-magnitude kinematical fluctuations and so tend to maintain their global properties. The same is true for a $\Lambda-$driven cosmos in such a state despite of exponential expansion. We outline relations to inflationary scenarios, and put the Dark Energy problem into perspective. Here, it is argued, on the grounds of the discussed cosmologies, that a classical explanation of Dark Energy through backreaction effects is theoretically conceivable, if the matter-dominated Universe emerged from a non-perturbative state in the vicinity of the stationary solution. We also discuss a number of caveats that furnish strong counter arguments in the framework of structure formation in a perturbed Friedmannian model.Comment: 33 pages, matches published version in Class. Quant. Gra

The bashful and the boastful : prestigious leaders and social change in Mesolithic Societies

The creation and maintenance of influential leaders and authorities is one of the key themes of archaeological and historical enquiry. However the social dynamics of authorities and leaders in the Mesolithic remains a largely unexplored area of study. The role and influence of authorities can be remarkably different in different situations yet they exist in all societies and in almost all social contexts from playgrounds to parliaments. Here we explore the literature on the dynamics of authority creation, maintenance and contestation in egalitarian societies, and discuss the implications for our interpretation and understanding of the formation of authorities and leaders and changing social relationships within the Mesolithic

The T1799A point mutation is present in posterior uveal melanoma

An activating mutation in exon 15 of the BRAF gene is present in a high proportion of cutaneous pigmented lesions. Until recently this mutation had however only been identified in one case of posterior uveal melanoma. Despite this apparent lack of the BRAF mutation, inappropriate downstream activation of the Ras/Raf/MAPK pathway has been described in posterior uveal melanoma. Based on the already recognised morphological and cytogenetic heterogeneity in uveal melanoma, we hypothesised that the BRAF mutation may be present in uveal melanoma but only in some of the tumour cells. In this study, we analysed 20 ciliary body and 30 choroidal melanomas using a nested PCR-based technique resulting in the amplification of a nested product only if the mutation was present. This sensitive technique can identify mutated DNA in the presence of wild-type DNA. The mutation was identified in 4 of 20 (20%) ciliary body and 11 of 30 (40%) choroidal melanomas. Further analysis of separate areas within the same choroidal melanoma demonstrated that the mutation was not present in the entire tumour. In conclusion, the T1799A BRAF mutation is present in a proportion of posterior uveal melanomas but within these tumours the distribution of the mutation is heterogeneous