Native Tertiary Structure and Nucleoside Modifications Suppress tRNA's Intrinsic Ability to Activate the Innate Immune Sensor PKR

Interferon inducible protein kinase PKR is an essential component of innate immunity. It is activated by long stretches of dsRNA and provides the first line of host defense against pathogens by inhibiting translation initiation in the infected cell. Many cellular and viral transcripts contain nucleoside modifications and/or tertiary structure that could affect PKR activation. We have previously demonstrated that a 5′-end triphosphate-a signature of certain viral and bacterial transcripts-confers the ability of relatively unstructured model RNA transcripts to activate PKR to inhibit translation, and that this activation is abrogated by certain modifications present in cellular RNAs. In order to understand the biological implications of native RNA tertiary structure and nucleoside modifications on PKR activation, we study here the heavily modified cellular tRNAs and the unmodified or the lightly modified mitochondrial tRNAs (mt-tRNA). We find that both a T7 transcript of yeast tRNAPhe and natively extracted total bovine liver mt-tRNA activate PKR in vitro, whereas native E. coli, bovine liver, yeast, and wheat tRNAPhe do not, nor do a variety of base- or sugar-modified T7 transcripts. These results are further supported by activation of PKR by a natively folded T7 transcript of tRNAPhe in vivo supporting the importance of tRNA modification in suppressing PKR activation in cells. We also examine PKR activation by a T7 transcript of the A14G pathogenic mutant of mt-tRNALeu, which is known to dimerize, and find that the misfolded dimeric form activates PKR in vitro while the monomeric form does not. Overall, the in vitro and in vivo findings herein indicate that tRNAs have an intrinsic ability to activate PKR and that nucleoside modifications and native RNA tertiary folding may function, at least in part, to suppress such activation, thus serving to distinguish self and non-self tRNA in innate immunity

Age at first birth in women is genetically associated with increased risk of schizophrenia

Prof. Paunio on PGC:n jäsenPrevious studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is -0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health.Peer reviewe

Search for H→γγ produced in association with top quarks and constraints on the Yukawa coupling between the top quark and the Higgs boson using data taken at 7 TeV and 8 TeV with the ATLAS detector

A search is performed for Higgs bosons produced in association with top quarks using the diphoton decay mode of the Higgs boson. Selection requirements are optimized separately for leptonic and fully hadronic final states from the top quark decays. The dataset used corresponds to an integrated luminosity of 4.5 fb−14.5 fb−1 of proton–proton collisions at a center-of-mass energy of 7 TeV and 20.3 fb−1 at 8 TeV recorded by the ATLAS detector at the CERN Large Hadron Collider. No significant excess over the background prediction is observed and upper limits are set on the tt¯H production cross section. The observed exclusion upper limit at 95% confidence level is 6.7 times the predicted Standard Model cross section value. In addition, limits are set on the strength of the Yukawa coupling between the top quark and the Higgs boson, taking into account the dependence of the tt¯H and tH cross sections as well as the H→γγ branching fraction on the Yukawa coupling. Lower and upper limits at 95% confidence level are set at −1.3 and +8.0 times the Yukawa coupling strength in the Standard Model

Androgen effects cause sex-biased impairment of CD8⁺ T cell antitumor activity.

Androgen signaling compromises CD8 <sup>+</sup> T cell effector functions and contributes to sex-biased outcomes in many forms of cancer (see the related Research Article by Kwon et al.)

Metabolic dynamics instruct CD8⁺ T-cell differentiation and functions.

Cytotoxic CD8 <sup>+</sup> T cells are a key element of the adaptative immune system to protect the organism against infections and malignant cells. During their activation and response, T cells undergo different metabolic pathways to support their energetic needs according to their localization and function. However, it has also been recently appreciated that this metabolic reprogramming also directly supports T-cell lineage differentiation. Accordingly, metabolic deficiencies and prolonged stress exposure can impact T-cell differentiation and skew them into an exhausted state. Here, we review how metabolism defines CD8 <sup>+</sup> T-cell differentiation and function. Moreover, we cover the principal metabolic dysregulation that promotes the exhausted phenotype under tumor or chronic virus conditions. Finally, we summarize recent strategies to reprogram impaired metabolic pathways to promote CD8 <sup>+</sup> T-cell effector function and survival

The Amsterdam pilot on bottom ash

In the summer of 2002, an experimental wet process was tested on 116 tons of bottom ash from the Amsterdam MSWI. The aim of the pilot was to demonstrate the feasibility of combining a washing step for improving the environmental quality of the ash with extensive metals recovery to meet the cost of the treatment. Bottom ashes from the incineration of household waste can be re-used as a building material for the foundation of roads, provided that the material does not leach contaminants, such as copper, to the environment. Washing the ash in the same way that contaminated soil is treated in soil remediation plants solves the leaching problem. The increased value of the building material and the non-ferrous metals extracted from it pay for the wet process

Multiphase and pore scale modeling on catalyst layer of high temperature polymer electrolyte membrane fuel cell

Phosphoric acid as the electrolyte in high temperature polymer electrolyte membrane fuel cell plays an essential role in its performance and lifetime. Maldistribution of phosphoric acid in the catalyst layer CL may result in performance degradation. In the present study, pore scale simulations were carried out to investigate phosphoric acid s multiphase flow in a cathode CL. A reconstructed CL model was built using focused ion beam SEM images, where distributions of pore, carbon support, binder, and catalyst particles can be identified. The multi relaxation time lattice Boltzmann method was employed to simulate phosphoric acid invading and leaching from the membrane into the CL during the membrane electrode assembly fabrication process. The predicted redistribution of phosphoric acid indicates that phosphoric acid of low viscosity or low wettability is prone to leaching into the CL. The effective transport properties and the active electrochemical active surface area ECSA were computed using a pore scale model. They were subsequently used in a macroscopic model to evaluate the cell performance. A parametric study shows that cell performance first increases with increasing phosphoric acid content due to the increase of ECSA. However, further increasing phosphoric acid content results in performance degradation due to mass transfer limitation caused by acid floodin