Pseudomonas expression of an oxygen sensing prolyl hydroxylase homologue regulates neutrophil host responses in vitro and in vivo

Background: Pseudomonas species are adapted to evade innate immune responses and can persist at sites of relative tissue hypoxia, including the mucus-plugged airways of patients with cystic fibrosis and bronchiectasis. The ability of these bacteria to directly sense and respond to changes in local oxygen availability is in part consequent upon expression of the 2-oxoglutarate oxygenase, Pseudomonas prolyl hydroxylase (PPHD), which acts on elongation factor Tu (EF-Tu), and is homologous with the human hypoxia inducible factor (HIF) prolyl hydroxylases. We report that PPHD expression regulates the neutrophil response to acute pseudomonal infection. Methods: In vitro co-culture experiments were performed with human neutrophils and PPHD-deficient and wild-type bacteria and supernatants, with viable neutrophil counts determined by flow cytometry. In vivo consequences of infection with PPHD deficient P. aeruginosa were determined in an acute pneumonia mouse model following intra-tracheal challenge. Results: Supernatants of PPHD-deficient bacterial cultures contained higher concentrations of the phenazine exotoxin pyocyanin and induced greater acceleration of neutrophil apoptosis than wild-type PAO1 supernatants in vitro. In vivo infection with PPHD mutants compared to wild-type PAO1 controls resulted in increased levels of neutrophil apoptosis and impaired control of infection, with higher numbers of P. aeruginosa recovered from the lungs of mice infected with the PPHD-deficient strain. This resulted in an overall increase in mortality in mice infected with the PPHD-deficient strain. Conclusions: Our data show that Pseudomonas expression of its prolyl hydroxylase influences the outcome of host-pathogen interactions in vitro and in vivo, demonstrating the importance of considering how both host and pathogen adaptations to hypoxia together define outcomes of infection. Given that inhibitors for the HIF prolyl hydroxylases are in late stage trials for the treatment of anaemia and that the active sites of PPHD and human HIF prolyl hydroxylases are closely related, the results are of current clinical interest

A recent rebuilding of most spirals ?

Re-examination of the properties of distant galaxies leads to the evidence that most present-day spirals have built up half of their stellar masses during the last 8 Gyr, mostly during several intense phases of star formation during which they took the appearance of luminous infrared galaxies (LIRGs). Distant galaxy morphologies encompass all of the expected stages of galaxy merging, central core formation and disk growth, while their cores are much bluer than those of present-day bulges. We have tested a spiral rebuilding scenario, for which 75+/-25% of spirals have experienced their last major merger event less than 8 Gyr ago. It accounts for the simultaneous decreases, during that period, of the cosmic star formation density, of the merger rate, of the number densities of LIRGs and of compact galaxies, while the densities of ellipticals and large spirals are essentially unaffected.Comment: (1) GEPI, Obs. Meudon, France ;(2)Max-Planck Institut fuer Astronomie, Germany (3) National Astronomical Observatories, CAS, China. Five pages, 1 figure. To be published in "Starbursts: From 30 Doradus to Lyman Break Galaxies", held in Cambridge, ed. R. de Grijs & R. M. Gonzalez Delgado (Dordrecht: Kluwer

Stripes, pseudogaps, and SO(6) in the cuprate superconductors

We briefly summarize two related calculations. First, we demonstrate that the instabilities (either nesting or pairing) associated with the high-T_c cuprates can be described by an SO(6) transformation group. There are two independent 6-dimensional representations (`superspins'). One superspin combines Zhang's 5-component superspin with a flux phase instability; the other involves a charge density wave, s-wave superconductivity, and an exotic spin current. The second calculation is a self-consistent slave boson calculation, which provides a good description of the doping dependence of the photoemission dispersion in terms of dynamic striped phases. The stripes are stabilized by strong electron-phonon coupling, and provide evidence for a doping-dependent crossover between the two superspin groundstates.Comment: 5 pages, 8 figures included as ps files; presented at SNS97 (Spectroscopies in Novel Superconductors), Sept. 14-18, Cape Cod; proceedings to appear in J. Phys. Chem. So

Stripes, Pseudogaps, and Van Hove Nesting in the Three-band tJ Model

Slave boson calculations have been carried out in the three-band tJ model for the high-T_c cuprates, with the inclusion of coupling to oxygen breathing mode phonons. Phonon-induced Van Hove nesting leads to a phase separation between a hole-doped domain and a (magnetic) domain near half filling, with long-range Coulomb forces limiting the separation to a nanoscopic scale. Strong correlation effects pin the Fermi level close to, but not precisely at the Van Hove singularity (VHS), which can enhance the tendency to phase separation. The resulting dispersions have been calculated, both in the uniform phases and in the phase separated regime. In the latter case, distinctly different dispersions are found for large, random domains and for regular (static) striped arrays, and a hypothetical form is presented for dynamic striped arrays. The doping dependence of the latter is found to provide an excellent description of photoemission and thermodynamic experiments on pseudogap formation in underdoped cuprates. In particular, the multiplicity of observed gaps is explained as a combination of flux phase plus charge density wave (CDW) gaps along with a superconducting gap. The largest gap is associated with VHS nesting. The apparent smooth evolution of this gap with doping masks a crossover from CDW-like effects near optimal doping to magnetic effects (flux phase) near half filling. A crossover from large Fermi surface to hole pockets with increased underdoping is found. In the weakly overdoped regime, the CDW undergoes a quantum phase transition ($T_{CDW}\to 0$), which could be obscured by phase separation.Comment: 15 pages, Latex, 18 PS figures Corrects a sign error: major changes, esp. in Sect. 3, Figs 1-4,6 replace

Cosmological parameter estimation using Very Small Array data out to ℓ= 1500

We estimate cosmological parameters using data obtained by the Very Small Array (VSA) in its extended configuration, in conjunction with a variety of other cosmic microwave background (CMB) data and external priors. Within the flat Λ cold dark matter (ΛCDM) model, we find that the inclusion of high-resolution data from the VSA modifies the limits on the cosmological parameters as compared to those suggested by the Wilkinson Microwave Anisotropy Probe (WMAP) alone, while still remaining compatible with their estimates. We find that Ωbh2= 0.0234+0.0012−0.0014, Ωdmh2= 0.111+0.014−0.016, h= 0.73+0.09−0.05, nS= 0.97+0.06−0.03, 1010AS= 23+7−3 and τ= 0.14+0.14−0.07 for WMAP and VSA when no external prior is included. On extending the model to include a running spectral index of density fluctuations, we find that the inclusion of VSA data leads to a negative running at a level of more than 95 per cent confidence ( nrun=−0.069 ± 0.032 ), something that is not significantly changed by the inclusion of a stringent prior on the Hubble constant. Inclusion of prior information from the 2dF galaxy redshift survey reduces the significance of the result by constraining the value of Ωm. We discuss the veracity of this result in the context of various systematic effects and also a broken spectral index model. We also constrain the fraction of neutrinos and find that fν < 0.087 at 95 per cent confidence, which corresponds to mν < 0.32 eV when all neutrino masses are equal. Finally, we consider the global best fit within a general cosmological model with 12 parameters and find consistency with other analyses available in the literature. The evidence for nrun < 0 is only marginal within this model

Common decisions made and actions taken during small-animal consultations at eight first-opinion practices in the United Kingdom

In order for veterinary surgeons to undertake an evidence-based approach to making decisions about theirpatients, it is important that new evidence is generated to support the clinical decision-making process.Many of the decisions are likely to be around the actions taken to treat or manage health problemsdiscussed during the consultation, and little is currently known about the factors which affect the typeof action taken. The aim of this study was to determine the decisions made and actions taken for healthproblems discussed during first-opinion small-animal consultations, as well as identifying factors whichmay affect the decision-making process.Data were gathered during direct observation of small-animal consultations conducted by 62 veterinarysurgeons in eight first-opinion practices in the United Kingdom. For each patient presented, data weregathered on all health problems discussed during the consultation. The decision made (whether an actionwas taken or not) and the action taken where applicable (e.g. therapeutic treatment with antibiotics) wasalso recorded. A three-level multivariable logistic-regression model was developed, with problem (Level1) nested within patient (Level 2) nested within consulting veterinary surgeon (Level 3), and a binaryoutcome variable of action versus no action.At least one action was taken for 69% (n = 2203/3192) of all problems discussed. Therapeutic treatmentwas the most common action taken (n = 1286/3192 problems; 40.3%), followed by management advice(n = 1040/3192; 32.6%) and diagnostic work-up (n = 323/3192; 10.1%). The most common therapeutictreatment was antibiotics (n = 386/1286; 30%), while the most common management advice given wasdietary advice (n = 509/1040; 48.9%). The three explanatory variables remaining in the final model werewhether the problem was a presenting or non-presenting problem, the type of diagnosis made, andthe body system affected. Explanatory variables which did not remain in the final model were patientsignalment, problem history, consultation type, clinical examination type, and who raised the problem(veterinary surgeon or owner).For over two-thirds of problems discussed, an action was taken which suggests these problems maybe seen as important by the veterinary surgeon and/or pet owner. No action was taken for almost a thirdof cases which could represent ‘watchful waiting’, which has been highlighted as important in humanhealthcare. Future research should focus on the common actions taken, further exploring the complexdecision-making process, and examining the effect of the decisions made on long-term patient outcomes

ELEVATED PHENYLACETIC ACID LEVELS DO NOT CORRELATE WITH ADVERSE EVENTS IN PATIENTS WITH UREA CYCLE DISORDERS OR HEPATIC ENCEPHALOPATHY AND CAN BE PREDICTED BASED ON THE PLASMA PAA TO PAGN RATIO

Background Phenylacetic acid (PAA) is the active moiety in sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB, HPN-100), both are approved for treatment of urea cycle disorders (UCDs) - rare genetic disorders characterized by hyperammonemia. PAA is conjugated with glutamine in the liver to form phenylacetyleglutamine (PAGN), which is excreted in urine. PAA plasma levels ≥500 μg/dL have been reported to be associated with reversible neurological adverse events (AEs) in cancer patients receiving PAA intravenously. Therefore, we have investigated the relationship between PAA levels and neurological AEs in patients treated with these PAA pro-drugs as well as approaches to identifying patients most likely to experience high PAA levels. Methods The relationship between nervous system AEs, PAA levels and the ratio of plasma PAA to PAGN were examined in 4683 blood samples taken serially from: [1] healthy adults [2], UCD patients ≥2 months of age, and [3] patients with cirrhosis and hepatic encephalopathy (HE). The plasma ratio of PAA to PAGN was analyzed with respect to its utility in identifying patients at risk of high PAA values. Results Only 0.2% (11) of 4683 samples exceeded 500 ug/ml. There was no relationship between neurological AEs and PAA levels in UCD or HE patients, but transient AEs including headache and nausea that correlated with PAA levels were observed in healthy adults. Irrespective of population, a curvilinear relationship was observed between PAA levels and the plasma PAA:PAGN ratio, and a ratio > 2.5 (both in μg/mL) in a random blood draw identified patients at risk for PAA levels > 500 μg/ml. Conclusions The presence of a relationship between PAA levels and reversible AEs in healthy adults but not in UCD or HE patients may reflect intrinsic differences among the populations and/or metabolic adaptation with continued dosing. The plasma PAA:PAGN ratio is a functional measure of the rate of PAA metabolism and represents a useful dosing biomarker

Observing the First Stars and Black Holes

The high sensitivity of JWST will open a new window on the end of the cosmological dark ages. Small stellar clusters, with a stellar mass of several 10^6 M_sun, and low-mass black holes (BHs), with a mass of several 10^5 M_sun should be directly detectable out to redshift z=10, and individual supernovae (SNe) and gamma ray burst (GRB) afterglows are bright enough to be visible beyond this redshift. Dense primordial gas, in the process of collapsing from large scales to form protogalaxies, may also be possible to image through diffuse recombination line emission, possibly even before stars or BHs are formed. In this article, I discuss the key physical processes that are expected to have determined the sizes of the first star-clusters and black holes, and the prospect of studying these objects by direct detections with JWST and with other instruments. The direct light emitted by the very first stellar clusters and intermediate-mass black holes at z>10 will likely fall below JWST's detection threshold. However, JWST could reveal a decline at the faint-end of the high-redshift luminosity function, and thereby shed light on radiative and other feedback effects that operate at these early epochs. JWST will also have the sensitivity to detect individual SNe from beyond z=10. In a dedicated survey lasting for several weeks, thousands of SNe could be detected at z>6, with a redshift distribution extending to the formation of the very first stars at z>15. Using these SNe as tracers may be the only method to map out the earliest stages of the cosmic star-formation history. Finally, we point out that studying the earliest objects at high redshift will also offer a new window on the primordial power spectrum, on 100 times smaller scales than probed by current large-scale structure data.Comment: Invited contribution to "Astrophysics in the Next Decade: JWST and Concurrent Facilities", Astrophysics & Space Science Library, Eds. H. Thronson, A. Tielens, M. Stiavelli, Springer: Dordrecht (2008

Observations of the High Redshift Universe

(Abridged) In these lectures aimed for non-specialists, I review progress in understanding how galaxies form and evolve. Both the star formation history and assembly of stellar mass can be empirically traced from redshifts z~6 to the present, but how the various distant populations inter-relate and how stellar assembly is regulated by feedback and environmental processes remains unclear. I also discuss how these studies are being extended to locate and characterize the earlier sources beyond z~6. Did early star-forming galaxies contribute significantly to the reionization process and over what period did this occur? Neither theory nor observations are well-developed in this frontier topic but the first results presented here provide important guidance on how we will use more powerful future facilities.Comment: To appear in `First Light in Universe', Saas-Fee Advanced Course 36, Swiss Soc. Astrophys. Astron. in press. 115 pages, 64 figures (see http://www.astro.caltech.edu/~rse/saas-fee.pdf for hi-res figs.) For lecture ppt files see http://obswww.unige.ch/saas-fee/preannouncement/course_pres/overview_f.htm