Evaluation of the cutaneous microbiome in psoriasis

Psoriasis, a highly prevalent disease of humans of unknown cause, is a chronic inflammatory disorder primarily involving skin, with distinctive clinical characteristics. With the newly developed tools that facilitate microbiome research, it now is possible to assess whether the cutaneous microbiome plays a role in the pathogenesis of this disorder. Preliminary data from our studies suggest that the cutaneous microbiome in psoriasis is complex and possibly different from normal. To deal with this complexity, we propose to examine the cutaneous microbiome in relation to psoriasis with explorations at several taxonomic and informatic levels. Our overall objective is to examine how changes in the normal cutaneous microbiome contributes to the pathogenesis of psoriasis. Since causality is complex and often difficult to prove, our overall hypothesis is that there are alterations in the cutaneous microbiome in areas of skin affected by psoriasis in comparison with the range observed in clinically unaffected areas, or in healthy persons. We also hypothesize that the characteristics of the microbiome may affect clinical responses to the immunomodulatory agents used to treat psoriasis. An alternative hypothesis is that effective treatment of psoriasis with systemic immunomodulatory agents will not substantially affect the disordered microbial ecosystem. Such observations would provide evidence for the roles of the microbiota in this disorder. Since an important consideration in microbiome research is the optimal level (e.g. phylum, genus, species, strain, gene) at which to examine a scientific question, and we are not yet certain what are the optimal levels for psoriasis, this also will be examined. Our studies of psoriasis should allow development of both approaches and tools that will have general utility for microbiome research. To test our hypothesis, we propose the following specific aims: 1. To understand the cutaneous microbiome species composition overlaying psoriatic lesions; 2. To investigate differences in metagenome content for psoriatic lesions compared to normal skin; 3. To identify differences in the transcriptional profiles of the microbiome and the host between normal skin and psoriatic lesions using high-throughput sequencing; and 4. To estimate the effects of systemic immunomodulatory therapy for psoriasis on microbiome composition. In total, these studies should help us understand the role of the microbiome in psoriasis pathogenesis

Clinical and molecular characterization of a cardiac ryanodine receptor founder mutation causing catecholaminergic polymorphic ventricular tachycardia

Background Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a difficult-to-diagnose cause of sudden cardiac death (SCD). We identified a family of 1400 individuals with multiple cases of CPVT, including 36 SCDs during youth. Objectives We sought to identify the genetic cause of CPVT in this family, to preventively treat and clinically characterize the mutation-positive individuals, and to functionally characterize the pathogenic mechanisms of the mutation. Methods Genetic testing was performed for 1404 relatives. Mutation-positive individuals were preventively treated with β-blockers and clinically characterized with a serial exercise treadmill test (ETT) and Holter monitoring. In vitro functional studies included caffeine sensitivity and store overload–induced calcium release activity of the mutant channel in HEK293 cells. Results We identified the p.G357S_RyR2 mutation, in the cardiac ryanodine receptor, in 179 family members and in 6 SCD cases. No SCD was observed among treated mutation-positive individuals over a median follow-up of 37 months; however, 3 relatives who had refused genetic testing (confirmed mutation-positive individuals) experienced SCD. Holter monitoring did not provide relevant information for CPVT diagnosis. One single ETT was unable to detect complex cardiac arrhythmias in 72% of mutation-positive individuals, though the serial ETT improved the accuracy. Functional studies showed that the G357S mutation increased caffeine sensitivity and store overload–induced calcium release activity under conditions that mimic catecholaminergic stress. Conclusion Our study supports the use of genetic testing to identify individuals at risk of SCD to undertake prophylactic interventions. We also show that the pathogenic mechanisms of p.G357S_RyR2 appear to depend on β-adrenergic stimulation

On the ongoing multiple blowout in NGC 604

Several facts regarding the structure of NGC 604 are examined here. The three main cavities, produced by the mechanical energy from massive stars which in NGC 604 are spread over a volume of 10$^6$ pc$^3$, are shown here to be undergoing blowout into the halo of M33. High resolution long slit spectroscopy is used to track the impact from massive stars while HST archive data is used to display the asymmetry of the nebula. NGC 604 is found to be a collection of photoionized filaments and sections of shells in direct contact with the thermalized matter ejected by massive stars. The multiple blowout events presently drain the energy injected by massive stars and thus the densest photoionized gas is found almost at rest and is expected to suffer a slow evolution.Comment: 15 pages (11 text), 4 figures. To be published in Ap

Plasticity of Repetitive DNA Sequences within a Bacterial (Type IV) Secretion System Component

DNA rearrangement permits bacteria to regulate gene content and expression. In Helicobacter pylori, cagY, which contains an extraordinary number of direct DNA repeats, encodes a surface-exposed subunit of a (type IV) bacterial secretory system. Examining potential DNA rearrangements involving the cagY repeats indicated that recombination events invariably yield in-frame open reading frames, producing alternatively expressed genes. In individual hosts, H. pylori cell populations include strains that produce CagY proteins that differ in size, due to the predicted in-frame deletions or duplications, and elicit minimal or no host antibody recognition. Using repetitive DNA, H. pylori rearrangements in a host-exposed subunit of a conserved bacterial secretion system may permit a novel form of antigenic evasion

The evolution of the X-ray luminosity functions of unabsorbed and absorbed AGNs out to z~5

We present new measurements of the evolution of the X-ray luminosity functions (XLFs) of unabsorbed and absorbed Active Galactic Nuclei (AGNs) out to z~5. We construct samples containing 2957 sources detected at hard (2-7 keV) X-ray energies and 4351 sources detected at soft (0.5-2 keV) energies from a compilation of Chandra surveys supplemented by wide-area surveys from ASCA} and ROSAT. We consider the hard and soft X-ray samples separately and find that the XLF based on either (initially neglecting absorption effects) is best described by a new flexible model parametrization where the break luminosity, normalization and faint-end slope all evolve with redshift. We then incorporate absorption effects, separately modelling the evolution of the XLFs of unabsorbed ($20<\log N_\mathrm{H}<22$) and absorbed ($22<\log N_\mathrm{H}<24$) AGNs, seeking a model that can reconcile both the hard- and soft-band samples. We find that the absorbed AGN XLF has a lower break luminosity, a higher normalization, and a steeper faint-end slope than the unabsorbed AGN XLF out to z~2. Hence, absorbed AGNs dominate at low luminosities, with the absorbed fraction falling rapidly as luminosity increases. Both XLFs undergo strong luminosity evolution which shifts the transition in the absorbed fraction to higher luminosities at higher redshifts. The evolution in the shape of the total XLF is primarily driven by the changing mix of unabsorbed and absorbed populations.Comment: 36 pages, 20 figures, 11 tables. A casual reader is directed to figures 7, 8, 9 and 20. Updated to version accepted for publication in MNRA

On the feedback from super stellar clusters. I. The structure of giant HII regions and HII galaxies

We review the structural properties of giant extragalactic HII regions and HII galaxies based on 2D hydrodynamic calculations, and propose an evolutionary sequence that accounts for their observed detailed structure. The model assumes a massive and young stellar cluster surrounded by a large collection of clouds. These are thus exposed to the most important star-formation feedback mechanisms: photoionization and the cluster wind. The models show how the two feedback mechanisms compete in the disruption of clouds and lead to two different hydrodynamic solutions: The storage of clouds into a long lasting ragged shell that inhibits the expansion of the thermalized wind, and the steady filtering of the shocked wind gas through channels carved within the cloud stratum. Both solutions are claimed to be concurrently at work in giant HII regions and HII galaxies, causing their detailed inner structure. This includes multiple large-scale shells, filled with an X-ray emitting gas, that evolve to finally merge with each other, giving the appearance of shells within shells. The models also show how the inner filamentary structure of the giant superbubbles is largely enhanced with matter ablated from clouds and how cloud ablation proceeds within the original cloud stratum. The calculations point at the initial contrast density between the cloud and the intercloud media as the factor that defines which of the two feedback mechanisms becomes dominant throughout the evolution. Animated version of the models can be found at http://www.iaa.csic.es/\~{}eperez/ssc/ssc.html.Comment: 28 pages, 10 figures, accepted for publication in the ApJ. Animated version of the models can be found at http://www.iaa.csic.es/\~{}eperez/ssc/ssc.htm

Testing Diagnostics of Nuclear Activity and Star Formation in Galaxies at z>1

We present some of the first science data with the new Keck/MOSFIRE instrument to test the effectiveness of different AGN/SF diagnostics at z~1.5. MOSFIRE spectra were obtained in three H-band multi-slit masks in the GOODS-S field, resulting in two hour exposures of 36 emission-line galaxies. We compare X-ray data with the traditional emission-line ratio diagnostics and the alternative mass-excitation and color-excitation diagrams, combining new MOSFIRE infrared data with previous HST/WFC3 infrared spectra (from the 3D-HST survey) and multiwavelength photometry. We demonstrate that a high [OIII]/Hb ratio is insufficient as an AGN indicator at z>1. For the four X-ray detected galaxies, the classic diagnostics ([OIII]/Hb vs. [NII]/Ha and [SII]/Ha) remain consistent with X-ray AGN/SF classification. The X-ray data also suggest that "composite" galaxies (with intermediate AGN/SF classification) host bona-fide AGNs. Nearly 2/3 of the z~1.5 emission-line galaxies have nuclear activity detected by either X-rays or the classic diagnostics. Compared to the X-ray and line ratio classifications, the mass-excitation method remains effective at z>1, but we show that the color-excitation method requires a new calibration to successfully identify AGNs at these redshifts.Comment: 7 pages, 4 figures. Accepted to ApJ Letter

Electron density contour maps via Rietveld-MEM analysis using HR-XRD for the polycrystalline ferroelectric BCZT

The maximum entropy method in combination with the Rietveld refinement method applied to the analysis (Rietveld-MEM analysis) of high-resolution x-ray diffraction (HR-XRD) is an important tool to elucidate the electron density distribution and chemical bonding nature of materials. In this work, we present the comparison of electron density distribution obtained from the Rietveld-MEM analysis for polycrystalline perovskite BaTiO3 (reference sample) and Ba0.9Ca0.2Ti0.9Zr0.1O3 (BCZT). To perform this task, HR-XRD patterns using synchrotron radiation were acquired. Tetragonal phase with P4mm (No.99) space group and pseudo-Voigt function were considered to model the HR-XRD peaks by the Rietveld method using the profile fitting Fullprof suite program. VESTA software was used to visualize 3D, 2D electron density distribution maps and line profiled to monitor the chemical bonding nature between Ba-O and Ti-O interactions and to visualize the off-center displacement of Ti cations by the incorporation of Zr and Ca cations. The interaction between Ti contours with O contours in the electron density distribution and the minimum electron density values revealed the enhancement of covalent nature and predominant ionic nature between barium and oxygen ions in the BCZT. To monitor the ferroelectric hysteresis behavior, polarization versus electric field curves complement the characterization of these samples