Identification of full length bovine TLR1 and functional characterization of lipopeptide recognition by bovine TLR2/1 heterodimer

Toll-like receptors (TLR) are highly conserved pattern recognition receptors of the innate immune system. Toll-like receptor 2 (TLR2) recognizes bacterial lipopeptides in a heterodimeric complex with TLR6 or TLR1, thereby discriminating between di- or triacylated lipopeptides, respectively. Previously, we found that HEK293 cells transfected with bovine TLR2 (boTLR2) were able to respond to diacylated lipopeptides but did not recognize triacylated lipopeptides, even after cotransfection with the so far published sequence of boTLR1. In this study we now could show that primary bovine cells were in general able to detect triacylated lipopetides. A closer investigation of the boTLR1 gene locus revealed an additional ATG 195 base pairs upstream from the published start codon. Its transcription would result in an N-terminus with high identity to human and murine TLR1 (huTLR1, muTLR1). Cloning and cotransfection of this longer boTLR1 with boTLR2 now resulted in the recognition of triacylated lipopeptides by HEK293 cells, thereby resembling the ex vivo observation. Analysis of the structure-activity relationship showed that the ester-bound acid chains of these lipopeptides need to consist of at least 12 carbon atoms to activate the bovine heterodimer showing similarity to the recognition by huTLR2/huTLR1. In contrast, HEK293 cell cotransfected with muTLR2 and muTLR1 could already be activated by lipopeptides with shorter fatty acids of only 6 carbon atoms. Thus, our data indicate that the additional N-terminal nucleotides belong to the full length and functionally active boTLR1 (boTLR1-fl) which participates in a species-specific recognition of bacterial lipopeptides

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Tools for computing the AGN feedback: radio-loudness distribution and the kinetic luminosity function

We studied the Active Galactic Nuclei (AGN) radio emission from a compilation of hard X-ray selected samples, all observed in the 1.4 GHz band. A total of more than 1600 AGN with 2-10 keV de-absorbed luminosities higher than 10^42 erg/s were used. For a sub-sample of about 50 z\lsim 0.1 AGN it was possible to reach a ~80% fraction of radio detections and therefore, for the first time, it was possible to almost completely measure the probability distribution function of the ratio between the radio and the X-ray luminosity Rx=log[L(1.4)/Lx]. The probability distribution function of Rx was functionally fitted as dependent on the X-ray luminosity and redshift, P(Rx|Lx,z). It roughly spans over 6 decades (-7<Rx<-1), and does not show any sign of bi-modality. It resulted that the probability of finding large values of the Rx ratio increases with decreasing X-ray luminosities and (possibly) with increasing redshift. No statistical significant difference was found between the radio properties of the X-ray absorbed and unabsorbed AGN. The measure of the probability distribution function of Rx allowed us to compute the kinetic luminosity function and the kinetic energy density which, at variance with what assumed in many galaxy evolution models, is observed to decrease of about a factor of five at redshift below 0.5. About half of the kinetic energy density results to be produced by the more radio quiet (Rx<-4) AGN. In agreement with previous estimates, the AGN efficiency in converting the accreted mass energy into kinetic power is, on average, ~5x10-3.Comment: 13 pages, ApJsty; ApJ in pres

General-relativistic model of hot accretion flows with global Compton cooling

We present a model of optically thin, two-temperature, accretion flows using an exact Monte Carlo treatment of global Comptonization, with seed photons from synchrotron and bremsstrahlung emission, as well as with a fully general relativistic description of both the radiative and hydrodynamic processes. We consider accretion rates for which the luminosities of the flows are between ~0.001 and 0.01 of the Eddington luminosity. The black hole spin parameter strongly affects the flow structure within the innermost 10 gravitational radii. The resulting large difference between the Coulomb heating in models with a non-rotating and a rapidly rotating black hole is, however, outweighed by a strong contribution of compression work, much less dependent on spin. The consequent reduction of effects related to the value of the black spin is more significant at smaller accretion rates. For a non-rotating black hole, the compressive heating of electrons dominates over their Coulomb heating, and results in an approximately constant radiative efficiency of approximately 0.4 per cent in the considered range of luminosities. For a rapidly rotating black hole, the Coulomb heating dominates, the radiative efficiency is ~1 per cent and it slightly increases (but less significantly than estimated in some previous works) with increasing accretion rate. We find an agreement between our model, in which the synchrotron emission is the main source of seed photons, and observations of black-hole binaries in their hard states and AGNs at low luminosities. In particular, our model predicts a hardening of the X-ray spectrum with increasing luminosity, as indeed observed below ~0.01 of the Eddington luminosity in both black-hole binaries and AGNs. Also, our model approximately reproduces the luminosity and the slope of the X-ray emission in Cen A.Comment: 13 pages, MNRAS, accepte

EGCG Prevents High Fat Diet-Induced Changes in Gut Microbiota, Decreases of DNA Strand Breaks, and Changes in Expression and DNA Methylation of Dnmt1

Obesity as a multifactorial disorder involves low-grade inflammation, increased reactive oxygen species incidence, gut microbiota aberrations, and epigenetic consequences. Thus, prevention and therapies with epigenetic active antioxidants, (-)-Epigallocatechin-3-gallate (EGCG), are of increasing interest. DNA damage, DNA methylation and gene expression of DNA methyltransferase 1, interleukin 6, and MutL homologue 1 were analyzed in C57BL/6J male mice fed a high-fat diet (HFD) or a control diet (CD) with and without EGCG supplementation. Gut microbiota was analyzed with quantitative real-time polymerase chain reaction. An induction of DNA damage was observed, as a consequence of HFD-feeding, whereas EGCG supplementation decreased DNA damage. HFD-feeding induced a higher inflammatory status. Supplementation reversed these effects, resulting in tissue specific gene expression and methylation patterns of DNA methyltransferase 1 and MutL homologue 1. HFD feeding caused a significant lower bacterial abundance. The Firmicutes/Bacteroidetes ratio is significantly lower in HFD + EGCG but higher in CD + EGCG compared to control groups. The results demonstrate the impact of EGCG on the one hand on gut microbiota which together with dietary components affects host health. On the other hand effects may derive from antioxidative activities as well as epigenetic modifications observed on CpG methylation but also likely to include other epigenetic elements

A stable and replicable neural signature of lifespan adversity in the adult brain

Environmental adversities constitute potent risk factors for psychiatric disorders. Evidence suggests the brain adapts to adversity, possibly in an adversity-type and region-specific manner. However, the long-term effects of adversity on brain structure and the association of individual neurobiological heterogeneity with behavior have yet to be elucidated. Here we estimated normative models of structural brain development based on a lifespan adversity profile in a longitudinal at-risk cohort aged 25 years (n = 169). This revealed widespread morphometric changes in the brain, with partially adversity-specific features. This pattern was replicated at the age of 33 years (n = 114) and in an independent sample at 22 years (n = 115). At the individual level, greater volume contractions relative to the model were predictive of future anxiety. We show a stable neurobiological signature of adversity that persists into adulthood and emphasize the importance of considering individual-level rather than group-level predictions to explain emerging psychopathology

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD