Mite-related bacterial antigens stimulate inflammatory cells in rosacea

Background Patients with papulopustular rosacea have a higher density of Demodex folliculorum mites on their faces than normal subjects but the role, if any, of their mites in initiating inflammation is disputed. Selective antibiotics are effective in reducing the inflammatory changes of papulopustular rosacea, but their mode of action is unknown. Objectives To investigate whether a D. folliculorum-related bacterium was capable of expressing antigens that could stimulate an inflammatory immune response in patients with rosacea. Methods A bacterium (Bacillus oleronius) was isolated from a D. folliculorum mite extracted from the face of a patient with papulopustular rosacea, and was investigated further. Results This bacterium produced antigens capable of stimulating peripheral blood mononuclear cells proliferation in 16 of 22 (73%) patients with rosacea but only five of 17 (29%) control subjects (P = 0�0105). This antigenic preparation was fractionated into 70 subfractions and the proteins in each fraction were visualized by sodium dodecyl sulphate�polyacrylamide gel electrophoresis. Western blot analysis revealed the presence of two antigenic proteins of size 62 and 83 kDa in fractions when probing with sera from patients with rosacea. No immunoreactivity to these proteins was recorded when probing with sera from control patients. Two-dimensional electrophoretic separation was used to isolate these proteins and matrix-assisted laser desorption �ionization time-of-flight analysis was employed to identify the relevant peptides. The 62-kDa immunoreactive protein shared amino acid sequence homology with an enzyme involved in carbohydrate metabolism and signal transduction while the 83-kDa protein was similar to bacterial heat shock proteins. Conclusions Antigenic proteins related to a bacterium (B. oleronius), isolated from a D. folliculorum mite, have the potential to stimulate an inflammatory response in patients with papulopustular rosacea

High-temperature order–disorder transitions in the skutterudites CoGe1.5Q1.5 (Q=S, Te)

The temperature dependence of anion ordering in the skutterudites CoGe1.5Q1.5 (Q=S, Te) has been investigated by powder neutron diffraction. Both materials adopt a rhombohedral structure at room temperature (space group R-3 ) in which the anions are ordered trans to each other within Ge2Q2 rings. In CoGe1.5S1.5, anion ordering is preserved up to the melting point of 950 °C. However, rhombohedral CoGe1.5Te1.5 undergoes a phase transition at 610 °C involving a change to cubic symmetry (space group Im-3). In the high-temperature modification, there is a statistical distribution of anions over the available sites within the Ge2Te2 rings. The structural transition involves a reduction in the degree of distortion of the Ge2Te2 rings which progressively transform from a rhombus to a rectangular shape. The effect of this transition on the thermoelectric properties has been investigated

Low-intermediate-temperature, high-pressure thermoelastic and crystallographic properties of thermoelectric clausthalite (PbSe-I)

The thermoelastic properties of the rock-salt structured thermoelectric lead selenide (clausthalite, PbSe-I) have been determined using neutron powder diffraction techniques for the temperature interval 10 - 500 K at ambient pressure, and 0 - 5.2 GPa at 298, and 150 K. Within this temperature range, lead selenide can be described using the same selfconsistent phenomenological model developed for the isostructural phases lead sulfide (PbS) and lead telluride (PbTe) in which the cations and anions behave as independent Debye oscillators (vibrational Debye temperatures of PbSe-I: Pb 111(1) K, Se 205(1) K). Simultaneous fitting of the unit cell volume and isochoric heat capacity to a two-term Debye internal energy function gives characteristic temperatures of 104(3) K and 219(5) K in excellent agreement with the two vibrational Debye temperatures derived from fitting the individual atomic displacement parameters. Grüneisen constants for the two term fits are 1.79 and 2.28 for the lower and upper characteristic temperature respectively. The calculated thermodynamic Grüneisen parameter increases monotonically from 2.03 at 10 K, to a maximum 2.22 at 100 K before decreasing back to 2.00 at 298 K and is broadly in agreement with the average of the two Grüneisen parameters associated with the two-term internal energy function. Despite the simplicity of the model, the calculated phonon density of states that is implicit within the two-term Debye model is found to show fair agreement with the full and partial vibrational densities of states derived from density functional theory (DFT). The bulk modulus and its pressure derivative at 298 K are 47.9(4) GPa and 5.4(2) respectively by fitting the pressure dependence of the unit cell volume to a 3rd order Birch- Murnaghan equation-of-state. For lower temperatures (T < 300 K) the high-pressure transition to PbSe-II is associated with a steep initial Clapeyron slope of 151 K GPa-1

Immunomodulation by imiquimod in patients with high-risk primary melanoma.

Imiquimod is a synthetic Toll-like receptor 7 (TLR7) agonist approved for the topical treatment of actinic keratoses, superficial basal cell carcinoma, and genital warts. Imiquimod leads to an 80-100% cure rate of lentigo maligna; however, studies of invasive melanoma are lacking. We conducted a pilot study to characterize the local, regional, and systemic immune responses induced by imiquimod in patients with high-risk melanoma. After treatment of the primary melanoma biopsy site with placebo or imiquimod cream, we measured immune responses in the treated skin, sentinel lymph nodes (SLNs), and peripheral blood. Treatment of primary melanomas with 5% imiquimod cream was associated with an increase in both CD4+ and CD8+ T cells in the skin, and CD4+ T cells in the SLN. Most of the CD8+ T cells in the skin were CD25 negative. We could not detect any increases in CD8+ T cells specifically recognizing HLA-A(*)0201-restricted melanoma epitopes in the peripheral blood. The findings from this small pilot study demonstrate that topical imiquimod treatment results in enhanced local and regional T-cell numbers in both the skin and SLN. Further research into TLR7 immunomodulating pathways as a basis for effective immunotherapy against melanoma in conjunction with surgery is warranted

The Accretion History of AGN: A Newly Defined Population of Cold Quasars

Quasars are the most luminous of active galactic nuclei (AGN), and are perhaps responsible for quenching star formation in their hosts. The Stripe 82X catalog covers 31.3 deg$^2$ of the Stripe 82 field, of which the 15.6 deg$^2$ covered with XMM-Newton is also covered by Herschel/SPIRE. We have 2500 X-ray detected sources with multi-wavelength counterparts, and 30% of these are unobscured quasars, with $L_X > 10^{44}\,$erg/s and $M_B < -23$. We define a new population of quasars which are unobscured, have X-ray luminosities in excess of $10^{44}\,$erg/s, have broad emission lines, and yet are also bright in the far-infrared, with a 250$\mu$m flux density of $S_{\rm 250}>30$mJy. We refer to these Herschel-detected, unobscured quasars as "Cold Quasars". A mere 4% (21) of the X-ray- and optically-selected unobscured quasars in Stripe 82X are detected at 250$\mu$m. These Cold Quasars lie at $z\sim1-3$, have $L_{\rm IR}>10^{12}\,L_\odot$, and have star formation rates of $\sim200-1400\,M_\odot$/yr. Cold Quasars are bluer in the mid-IR than the full quasar population, and 72% of our Cold Quasars have WISE W3 $<$ 11.5 [Vega], while only 19% of the full quasar sample meets this criteria. Crucially, Cold Quasars have on average $\sim9\times$ as much star formation as the main sequence of star forming galaxies at similar redshifts. Although dust-rich, unobscured quasars have occasionally been noted in the literature before, we argue that they should be considered as a separate class of quasars due to their high star formation rates. This phase is likely short-lived, as the central engine and immense star formation consume the gas reservoir. Cold Quasars are type-1 blue quasars that reside in starburst galaxies.Comment: Accepted for publication in Ap

Influence of coding variability in APP-Aß metabolism genes in sporadic Alzheimer's disease

The cerebral deposition of Aß42, a neurotoxic proteolitic derivate of amyloid precursor protein (APP), is a central event in Alzheimer’s disease (AD)(Amyloid hypothesis). Given the key role of APP-Aß metabolism in AD pathogenesis, we selected 29 genes involved in APP processing, Aß degradation and clearance. We then used exome and genome sequencing to investigate the single independent (single-variant association test) and cumulative (gene-based association test) effect of coding variants in these genes as potential susceptibility factors for AD, in a cohort composed of 435 sporadic and mainly late-onset AD cases and 801 elderly controls from North America and the UK. Our study shows that common coding variability in these genes does not play a major role for the disease development. In the single-variant association analysis, the main hits, which were nominally significant, were found to be very rare coding variants (MAF 0.3%-0.8%) that map to genes involved in APP processing (MEP1B), trafficking and recycling (SORL1), Aß extracellular degradation (ACE) and clearance (LRP1). Moreover, four genes (ECE1, LYZ, TTR and MME) have been found as nominally associated to AD using c-alpha and SKAT tests. We suggest that Aβ degradation and clearance, rather than Aβ production, may play a crucial role in the etiology of sporadic AD

Overview of the CCP4 suite and current developments.

The CCP4 (Collaborative Computational Project, Number 4) software suite is a collection of programs and associated data and software libraries which can be used for macromolecular structure determination by X-ray crystallography. The suite is designed to be flexible, allowing users a number of methods of achieving their aims. The programs are from a wide variety of sources but are connected by a common infrastructure provided by standard file formats, data objects and graphical interfaces. Structure solution by macromolecular crystallography is becoming increasingly automated and the CCP4 suite includes several automation pipelines. After giving a brief description of the evolution of CCP4 over the last 30 years, an overview of the current suite is given. While detailed descriptions are given in the accompanying articles, here it is shown how the individual programs contribute to a complete software package