Genetic variation of TLR4 influences immunoendocrine stress response: an observational study in cardiac surgical patients

Introduction: Systemic inflammation (e.g. following surgery) involves Toll-like receptor (TLR) signaling and leads to an endocrine stress response. This study aims to investigate a possible influence of TLR2 and TLR4 single nucleotide polymorphisms (SNPs) on perioperative adrenocorticotropic hormone (ACTH) and cortisol regulation in serum of cardiac surgical patients. To investigate the link to systemic inflammation in this context, we additionally measured 10 different cytokines in the serum. Methods: 338 patients admitted for elective cardiac surgery were included in this prospective observational clinical cohort study. Genomic DNA of patients was screened for TLR2 and TLR4 SNPs. Serum concentrations of ACTH, cortisol, interferon (IFN)-, interleukin (IL)-1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)- and granulocyte macro-phage-colony stimulating factor (GM-CSF) were determined before surgery, immediately post surgery and on the first postoperative day. Results: 13 patients were identified as TLR2 SNP carrier, 51 as TLR4 SNP carrier and 274 pa-tients as non-carrier. Basal levels of ACTH, cortisol and cytokines did not differ between groups. In all three groups a significant, transient perioperative rise of cortisol could be ob-served. However, only in the non-carrier group this was accompanied by a significant ACTH rise, TLR4 SNP carriers had significant lower ACTH levels compared to non-carriers ((mean[95% confidence intervals]) non-carriers: 201.9[187.7 to 216.1]pg/ml; TLR4 SNP car-riers: 149.9[118.4 to 181.5]pg/ml; TLR2 SNP carriers: 176.4[110.5 to 242.3]pg/ml). Compared to non-carriers, TLR4 SNP carriers showed significant lower serum IL-8, IL-10 and GM-CSF peaks ((mean[95% confidence intervals]): IL-8: non-carriers: 42.6[36.7 to 48.5]pg/ml, TLR4 SNP carriers: 23.7[10.7 to 36.8]pg/ml; IL-10: non-carriers: 83.8[70.3 to 97.4]pg/ml, TLR4 SNP carriers: 54.2[24.1 to 84.2]pg/ml; GM-CSF: non-carriers: 33.0[27.8 to 38.3]pg/ml, TLR4 SNP carriers: 20.2[8.6 to 31.8]pg/ml). No significant changes over time or between the groups were found for the other cytokines. Conclusions: Regulation of the immunoendocrine stress response during systemic inflamma-tion is influenced by the presence of a TLR4 SNP. Cardiac surgical patients carrying this ge-notype showed decreased serum concentrations of ACTH, IL-8, IL-10 and GM-CSF. This finding might have impact on interpreting previous and designing future trials on diagnosing and modulating immunoendocrine dysregulation (e.g. adrenal insufficiency) during systemic inflammation and sepsis

First evidence for STING SNP R293Q being protective regarding obesity-associated cardiovascular disease in age-advanced subjects - a cohort study

Obesity is a risk factor for several aging-related diseases such as type 2 diabetes, cardiovascular disease, and cancer. Especially, cardiovascular disease is triggered by obesity by inducing vascular senescence and chronic low-grade systemic inflammation, also known as inflamm-aging. Released molecules from damaged cells and their recognition by the innate immune system is one of the mechanisms driving inflamm-aging. Obesity results in mitochondrial damage, leading to endothelial inflammation triggered by cytosolic mtDNA via the cGAS/STING pathway. Recently, we have shown STING SNP R293Q to be associated with a decreased risk for aging-related diseases in current smokers. Since current smoking triggers DNA damage that, similar to obesity, may result in the release of DNA into the cytoplasm, we hypothesized that the cGAS/STING pathway can modify the phenotype of aging also in obese subjects. Therefore, the objective of our study was to investigate whether STING R293Q is associated with aging-related diseases in obese individuals. We indeed show that STING 293Q is associated with protection from combined aging-related diseases (P = 0.014) and, in particular, cardiovascular disease in these subjects (P = 0.010). Therefore, we provide the first evidence that stratification for obesity may reveal new genetic loci determining the risk for aging-related diseases

Metallicity and Far-Infrared Luminosity of High Redshift Quasars

We present the results of an exploratory study of broad line region (BLR) metallicity in 34 2.2 < z < 4.6 quasars with far-infrared (FIR) luminosities (L_FIR) from 10^13.4 to 10^12.1 L_\odot . Quasar samples sorted by L_FIR might represent an evolutionary sequence if the star formation rates (SFRs) in quasar hosts generally diminish across quasar lifetimes. We use rest-frame ultraviolet spectra from the Sloan Digital Sky Survey to construct three composite spectra sorted by L_FIR, corresponding to average SFRs of 4980, 2130 and 340 M_\odot yr^-1 after correcting for a nominal quasar FIR contribution. The measured N V {\lambda} 1240/C IV {\lambda} 1550 and Si IV {\lambda} 1397+O IV] {\lambda} 1402/C IV {\lambda} 1550 emission line ratios indicate super-solar BLR metallicities in all three composites, with no evidence for a trend with the star formation rate. The formal derived metallicities, Z ~ 5-9 Z_\odot , are similar to those derived for the BLRs of other quasars at similar redshifts and luminosities. These results suggest that the ongoing star formation in the host is not responsible for the metal enrichment of the BLR gas. Instead, the BLR gas must have been enriched before the visible quasar phase. These results for high quasar metallicities, regardless of L_FIR, are consistent with evolution scenarios wherein visibly bright quasars appear after the main episode(s) of star formation and metal enrichment in the host galaxies. Finally, young quasars, those more closely associated with a recent merger or a blowout of gas and dust, may exhibit tracers of these events, such as redder continuum slopes and higher incidence of narrow absorption lines. With the caveat of small sample sizes, we find no relation between L_FIR and the reddening or the incidence of absorption lines.Comment: 10 pages, 3 figures. Accepted to MNRAS, May 201

TLR-6 SNP P249S is associated with healthy aging in nonsmoking Eastern European Caucasians - A cohort study

Background To investigate mechanisms that determine healthy aging is of major interest in the modern world marked by longer life expectancies. In addition to lifestyle and environmental factors genetic factors also play an important role in aging phenotypes. The aged immune system is characterized by a chronic micro-inflammation, known as inflamm-aging, that is suspected to trigger the onset of age-related diseases such as cardiovascular disease, Alzheimer’s disease, cancer, and Diabetes Mellitus Type 2 (DMT2). We have recently shown that a Toll-like receptor 6 variant (P249S) is associated with susceptibility to cardiovascular disease and speculated that this variant may also be associated with healthy aging in general by decreasing the process of inflamm- aging. Results Analyzing the PolSenior cohort we show here that nonsmoking S allele carriers are significantly protected from age-related diseases (P = 0.008, OR: 0.654). This association depends not only on the association with cardiovascular diseases (P = 0.018, OR: 0.483) for homozygous S allele carriers, but is also driven by a protection from Diabetes Mellitus type 2 (P = 0.010, OR: 0.486) for S allele carriers. In addition we detect a trend but no significant association of this allele with inflamm-aging in terms of baseline IL-6 levels. Conclusion We confirm our previous finding of the TLR-6 249S variant to be protective regarding cardiovascular diseases. Furthermore, we present first evidence of TLR-6 249S being involved in DMT2 susceptibility and may be in general associated with healthy aging possibly by reducing the process of inflamm-aging

The mass-metallicity relation of SDSS quasars

Active galactic nuclei (AGNs) are characterized by a clear correlation between luminosity and metallicity (L_AGN-Z_AGN relation). The origin of this correlation is not clear. It may result from a relation between the black hole mass (M_BH) and metallicity, or from a relation between the accretion rate (L/L_Edd) and metallicity. To investigate the origin of the L_AGN-Z_AGN relation, we use optical spectra of 2383 quasars at 2.3 < z < 3.0 from the Sloan Digital Sky Survey. By using this data set, we have constructed composite spectra of 33 subsamples in intervals of both M_BH and L/L_Edd. From these composite spectra we measure emission-line flux ratios that are sensitive to the metallicity of the broad line region (BLR); specifically, NV/CIV, NV/HeII, (SiIV+OIV])/CIV, and AlIII/CIV. We find that there is a significant correlation between M_BH and Z_BLR as inferred from all four metallicity-sensitive emission-line flux ratios. This result strongly suggests that the observed L_AGN-Z_AGN relation is mostly a consequence of the M_BH-Z_AGN relation. The relation between M_BH and Z_BLR is likely a consequence of both the M_BH-M_bul relation and of the mass-metallicity relation in the host galaxy. We also find that L/L_Edd correlates with the emission line flux ratios involving NV (more specifically, NV/CIV and NV/HeII), while it does not correlate with the other two metallicity sensitive emission line flux ratios, i.e., (SiIV+OIV])/CIV and AlIII/CIV. These correlations indicate that the emission-line flux ratios involving NV depend on both metallicity and relative abundance of nitrogen. We suggest that the relation between L/L_Edd and those line ratios involving nitrogen, is caused by a delay of the black hole accretion rate relative to the onset of nuclear star formation of about 10^8 years, which is the timescale required for the nitrogen enrichment.Comment: Accepted for publication in A&A, 16 pages, 6 figure

Weak 13CO in the Cloverleaf Quasar: evidence for a young, early generation starburst

Observations of 12CO at high redshift indicate rapid metal enrichment in the nuclear regions of at least some galaxies in the early universe. However, the enrichment may be limited to nuclei that are synthesized by short-lived massive stars, excluding classical secondary nuclei like 13CO. Testing this idea, we tentatively detect the 13CO J=3-2 line at a level of 0.3 Jy km/s toward the Cloverleaf Quasar at redshift 2.5. This is the first observational evidence for 13CO at high redshift. The 12CO/13CO J=3-2 luminosity ratio is with at least 40 much higher than ratios observed in molecular clouds of the Milky Way and in the ultraluminous galaxy Arp 220, but may be similar to that observed toward NGC 6240. Large Velocity Gradient (LVG) models simulating seven 12CO transitions and the 13CO line yield 12CO/13CO abundance ratios in excess of 100 for the Cloverleaf. It is possible that the measured ratio is affected by a strong submillimeter radiation field, which reduces the contrast between the 13CO line and the background. It is more likely, however, that the ratio is caused by a real deficiency of 13CO. A potential conflict with optical data, indicating high abundances also for secondary nuclei in quasars of high redshift, may be settled if the bulk of the CO emission is originating sufficiently far from the active galactic nucleus.Comment: 7 pages, 5 figures, accepted for publication in A&A (Main Journal

Characterization of Structural Defects in (Cd,Zn)Te Crystals Grown by the Travelling Heater Method

Structural defects and compositional uniformity remain the major problems affecting the performance of (Cd, Zn)Te (CZT) based detector devices. Understanding the mechanism of growth and defect formation is therefore fundamental to improving the crystal quality. In this frame, space experiments for the growth of CZT by the Travelling Heater Method (THM) under microgravity are scheduled. A detailed ground-based program was performed to determine experimental parameters and three CZT crystals were grown by the THM. The structural defects, compositional homogeneity and resistivity of these ground-based crystals were investigated. A ZnTe content variation was observed at the growth interface and a high degree of stress associated with extensive dislocation networks was induced, which propagated into the grown crystal region according to the birefringence and X-ray White Beam Topography (XWBT) results. By adjusting the growth parameters, the ZnTe variations and the resulting stress were efficiently reduced. In addition, it was revealed that large inclusions and grain boundaries can generate a high degree of stress, leading to the formation of dislocation slip bands and subgrain boundaries. The dominant defects, including grain boundaries, dislocation networks and cracks in the interior of crystals, led to the resistivity variation in the crystals. The bulk resistivity of the as-grown crystals ranged from 109 Ωcm to 1010 Ωcm

Microlensing in H1413+117 : disentangling line profile emission and absorption in a broad absorption line quasar

On the basis of 16 years of spectroscopic observations of the four components of the gravitationally lensed broad absorption line (BAL) quasar H1413+117, covering the ultraviolet to visible rest-frame spectral range, we analyze the spectral differences observed in the P Cygni-type line profiles and have used the microlensing effect to derive new clues to the BAL profile formation. We confirm that the spectral differences observed in component D can be attributed to a microlensing effect lasting at least a decade. We show that microlensing magnifies the continuum source in image D, leaving the emission line region essentially unaffected. We interpret the differences seen in the absorption profiles of component D as the result of an emission line superimposed onto a nearly black absorption profile. We also find that the continuum source and a part of the broad emission line region are likely de-magnified in component C, while components A and B are not affected by microlensing. We show that microlensing of the continuum source in component D has a chromatic dependence compatible with the thermal continuum emission of a standard Shakura-Sunyaev accretion disk. Using a simple decomposition method to separate the part of the line profiles affected by microlensing and coming from a compact region from the part unaffected by this effect and coming from a larger region, we disentangle the true absorption line profiles from the true emission line profiles. The extracted emission line profiles appear double-peaked, suggesting that the emission is occulted by a strong absorber, narrower in velocity than the full absorption profile, and emitting little by itself. We propose that the outflow around H1413+117 is constituted by a high-velocity polar flow and a denser, lower velocity disk seen nearly edge-on.Comment: Accepted for publication in Astronomy and Astrophysic

The common HAQ STING variant impairs cGAS-dependent antibacterial responses and is associated with susceptibility to Legionnaires’ disease in humans

Abstract The cyclic GMP-AMP synthase (cGAS)-STING pathway is central for innate immune sensing of various bacterial, viral and protozoal infections. Recent studies identified the common HAQ and R232H alleles of TMEM173/STING, but the functional consequences of these variants for primary infections are unknown. Here we demonstrate that cGAS- and STING-deficient murine macrophages as well as human cells of individuals carrying HAQ TMEM173/STING were severely impaired in producing type I IFNs and pro-inflammatory cytokines in response to Legionella pneumophila, bacterial DNA or cyclic dinucleotides (CDNs). In contrast, R232H attenuated cytokine production only following stimulation with bacterial CDN, but not in response to L. pneumophila or DNA. In a mouse model of Legionnaires’ disease, cGAS- and STING-deficient animals exhibited higher bacterial loads as compared to wild-type mice. Moreover, the haplotype frequency of HAQ TMEM173/STING, but not of R232H TMEM173/STING, was increased in two independent cohorts of human Legionnaires’ disease patients as compared to healthy controls. Our study reveals that the cGAS-STING cascade contributes to antibacterial defense against L. pneumophila in mice and men, and provides important insight into how the common HAQ TMEM173/STING variant affects antimicrobial immune responses and susceptibility to infection. Trial registration ClinicalTrials.gov DRKS00005274, German Clinical Trials Register Author summary Interferons (IFNs) and pro-inflammatory cytokines are key regulators of gene expression and antibacterial defense during Legionella pneumophila infection. Here we demonstrate that production of these mediators was largely or partly dependent on the cyclic GMP-AMP synthase (cGAS)-STING pathway in human and murine cells. Cells of individuals carrying the common HAQ allele of TMEM173/STING were strongly impaired in their ability to respond to L. pneumophila, bacterial DNA or cyclic dinucleotides (CDNs), whereas the R232H allele was only attenuated in sensing of exogenous CDNs. Importantly, cGAS and STING contributed to antibacterial defense in mice during L. pneumophila lung infection, and the allele frequency of HAQ TMEM173/STING, but not of R232H TMEM173/STING, was increased in two independent cohorts of human Legionnaires’ disease patients as compared to healthy controls. Hence, sensing of bacterial DNA by the cGAS/STING pathway contributes to antibacterial defense against L. pneumophila infection, and the hypomorphic variant HAQ TMEM173/STING is associated with increased susceptibility to Legionnaires’ disease in humans