Cucumber mosaic virus and its 2b protein alter emission of host volatile organic compounds but not aphid vector settling in tobacco

Aphids, including the generalist herbivore Myzus persicae, transmit cucumber mosaic virus (CMV). CMV (strain Fny) infection affects M. persicae feeding behavior and performance on tobacco (Nicotiana tabacum), Arabidopsis thaliana and cucurbits in varying ways. In Arabidopsis and cucurbits, CMV decreases host quality and inhibits prolonged feeding by aphids, which may enhance virus transmission rates. CMV-infected cucurbits also emit deceptive, aphid-attracting volatiles, which may favor virus acquisition. In contrast, aphids on CMV-infected tobacco (cv. Xanthi) exhibit increased survival and reproduction. This may not increase transmission but might increase virus and vector persistence within plant communities. The CMV 2b counter-defense protein diminishes resistance to aphid infestation in CMV-infected tobacco plants. We hypothesised that in tobacco CMV and its 2b protein might also alter the emission of volatile organic compounds that would influence aphid behavior

The MS Remyelinating Drug Bexarotene (an RXR Agonist) Promotes Induction of Human Tregs and Suppresses Th17 Differentiation <i>In Vitro</i>.

Funder: Biotechnology and Biological Sciences Research CouncilFunder: Wellcome TrustFunder: NIHR Cambridge Biomedical Research CentreThe retinoid X receptor agonist bexarotene promotes remyelination in patients with multiple sclerosis. Murine studies have also demonstrated that RXR agonists have anti-inflammatory effects by enhancing the ability of all-trans-retinoic acid (atRA) to promote T-regulatory cell (Treg) induction and reduce Th17 differentiation in vitro. By stimulating human naïve CD4 T-cells in the presence of Treg or Th17 skewing cytokines, we show that bexarotene also tips the human Treg/Th17 axis in favor of Treg induction, but unlike murine cells this occurs independently of atRA and retinoic acid receptor signaling. Tregs induced in the presence of bexarotene express canonical markers of T-regulation and are functionally suppressive in vitro. Circulating Treg numbers did not increase in the blood of trial patients receiving bexarotene; we believe this is because Treg induction is likely to occur within tissues. These findings lend support to developing RXR agonists as treatments of autoimmune diseases, in particular multiple sclerosis

Coinfections by noninteracting pathogens are not independent and require new tests of interaction.

If pathogen species, strains, or clones do not interact, intuition suggests the proportion of coinfected hosts should be the product of the individual prevalences. Independence consequently underpins the wide range of methods for detecting pathogen interactions from cross-sectional survey data. However, the very simplest of epidemiological models challenge the underlying assumption of statistical independence. Even if pathogens do not interact, death of coinfected hosts causes net prevalences of individual pathogens to decrease simultaneously. The induced positive correlation between prevalences means the proportion of coinfected hosts is expected to be higher than multiplication would suggest. By modelling the dynamics of multiple noninteracting pathogens causing chronic infections, we develop a pair of novel tests of interaction that properly account for nonindependence between pathogens causing lifelong infection. Our tests allow us to reinterpret data from previous studies including pathogens of humans, plants, and animals. Our work demonstrates how methods to identify interactions between pathogens can be updated using simple epidemic models

Interplay between base excision repair protein XRCC1 and ALDH2 predicts overall survival in lung and liver cancer patients.

Background To deliver efficacious personalised cancer treatment, it is essential to characterise the cellular metabolism as well as the genetic stability of individual tumours. In this study, we describe a new axis between DNA repair and detoxification of aldehyde derivatives with important implications for patient prognosis and treatment.Methods Western blot and qPCR analyses were performed in relevant non-transformed and cancer cell lines from lung and liver tissue origin in combination with bioinformatics data mining of The Cancer Genome Atlas database from lung and hepatocellular cancer patients.Results Using both biochemical and bioinformatics approaches, we revealed an association between the levels of expression of the aldehyde detoxifying enzyme aldehyde dehydrogenase 2 (ALDH2) and the key DNA base excision repair protein XRCC1. Across cancer types, we found that if one of the corresponding genes exhibits a low expression level, the level of the other gene is increased. Surprisingly, we found that low ALDH2 expression levels associated with high XRCC1 expression levels are indicative for a poor overall survival, particularly in lung and liver cancer patients. In addition, we found that Mithramycin A, a XRCC1 expression inhibitor, efficiently kills cancer cells expressing low levels of ALDH2.Conclusions Our data suggest that lung and liver cancers require efficient single-strand break repair for their growth in order to benefit from a low aldehyde detoxification metabolism. We also propose that the ratio of XRCC1 and ALDH2 levels may serve as a useful prognostic tool in these cancer types

Transition from Fireball to Poynting-flux-dominated Outflow in Three-Episode GRB 160625B

The ejecta composition is an open question in gamma-ray bursts (GRB) physics. Some GRBs possess a quasi-thermal spectral component in the time-resolved spectral analysis, suggesting a hot fireball origin. Others show a featureless non-thermal spectrum known as the "Band" function, consistent with a synchrotron radiation origin and suggesting that the jet is Poynting-flux-dominated at the central engine and likely in the emission region as well. There are also bursts showing a sub-dominant thermal component and a dominant synchrotron component suggesting a likely hybrid jet composition. Here we report an extraordinarily bright GRB 160625B, simultaneously observed in gamma-rays and optical wavelengths, whose prompt emission consists of three isolated episodes separated by long quiescent intervals, with the durations of each "sub-burst" being $\sim$ 0.8 s, 35 s, and 212 s, respectively. Its high brightness (with isotropic peak luminosity L$_{\rm p, iso}\sim 4\times 10^{53}$ erg/s) allows us to conduct detailed time-resolved spectral analysis in each episode, from precursor to main burst and to extended emission. The spectral properties of the first two sub-bursts are distinctly different, allowing us to observe the transition from thermal to non-thermal radiation between well-separated emission episodes within a single GRB. Such a transition is a clear indication of the change of jet composition from a fireball to a Poynting-flux-dominated jet.Comment: Revised version reflecting the referees' comments. 27 pages, 11 figures, 5 tables. The final edited version will appear in Nature Astronom

REMIR: The REM infrared camera to follow up the early phases of GRBs afterglows

REMIR is a near-infrared camera, covering the 0.95–2.3 μm range with 5 filters (z,J,H,Ks and H2), mounted at one of the Nasmyth foci of the REM (Rapid Eye Mount) telescope. REM is a fully robotic fast-slewing 60 cm telescope, primarily designed to follow-up the early phases of the afterglow of GRBs detected by dedicated instruments onboard satellites (like SWIFT, a satellite entirely dedicated to GRBs science launched the 12 November 2004). Moreover REM hosts a slitless spectrograph covering the range 0.45–0.95 μm, with 30 sample points and with the possibility to perform broad-band V,R,I photometry (ROSS, REM Optical Slitless Spectrograph). The main task of REMIR is to perform realtime NIR observations of GRBs detected by gamma-ray monitors onboard satellites, looking for any possible infrared transient source. As soon as a transient source is detected in the IR images, larger telescopes are promptly alerted to perform early spectroscopy of the afterglow. All the above operations are performed in a fully automatic way and without any human supervision. We present the results of on-site tests that have been done to characterize the REMIR camera and the performances of the dedicated reduction pipeline AQuA (Automatic Quick Analysis), suited for fast transients detection

Safety and efficacy of bexarotene in patients with relapsing-remitting multiple sclerosis (CCMR One): a randomised, double-blind, placebo-controlled, parallel-group, phase 2a study

Background: Progressive disability in multiple sclerosis occurs because CNS axons degenerate as a late consequence of demyelination. In animals, retinoic acid receptor RXR-gamma agonists promote remyelination. We aimed to assess the safety and efficacy of a non-selective retinoid X receptor agonist in promoting remyelination in people with multiple sclerosis. Methods: This randomised, double-blind, placebo-controlled, parallel-group, phase 2a trial (CCMR One) recruited patients with relapsing-remitting multiple sclerosis from two centres in the UK. Eligible participants were aged 18–50 years and had been receiving dimethyl fumarate for at least 6 months. Via a web-based system run by an independent statistician, participants were randomly assigned (1:1), by probability-weighted minimisation using four binary factors, to receive 300 mg/m2 of body surface area per day of oral bexarotene or oral placebo for 6 months. Participants, investigators, and outcome assessors were masked to treatment allocation. MRI scans were done at baseline and at 6 months. The primary safety outcome was the number of adverse events and withdrawals attributable to bexarotene. The primary efficacy outcome was the patient-level change in mean lesional magnetisation transfer ratio between baseline and month 6 for lesions that had a baseline magnetisation transfer ratio less than the within-patient median. We analysed the primary safety outcome in the safety population, which comprised participants who received at least one dose of their allocated treatment. We analysed the primary efficacy outcome in the intention-to-treat population, which comprised all patients who completed the study. This study is registered in the ISRCTN Registry, 14265371, and has been completed. Findings: Between Jan 17, 2017, and May 17, 2019, 52 participants were randomly assigned to receive either bexarotene (n=26) or placebo (n=26). Participants who received bexarotene had a higher mean number of adverse events (6·12 [SD 3·09]; 159 events in total) than did participants who received placebo (1·63 [SD 1·50]; 39 events in total). All bexarotene-treated participants had at least one adverse event, which included central hypothyroidism (n=26 vs none on placebo), hypertriglyceridaemia (n=24 vs none on placebo), rash (n=13 vs one on placebo), and neutropenia (n=10 vs none on placebo). Five (19%) participants on bexarotene and two (8%) on placebo discontinued the study drug due to adverse events. One episode of cholecystitis in a placebo-treated participant was the only serious adverse event. The change in mean lesional magnetisation transfer ratio was not different between the bexarotene group (0·25 percentage units [pu; SD 0·98]) and the placebo group (0·09 pu [0·84]; adjusted bexarotene–placebo difference 0·16 pu, 95% CI –0·39 to 0·71; p=0·55). Interpretation: We do not recommend the use of bexarotene to treat patients with multiple sclerosis because of its poor tolerability and negative primary efficacy outcome. However, statistically significant effects were seen in some exploratory MRI and electrophysiological analyses, suggesting that other retinoid X receptor agonists might have small biological effects that could be investigated in further studies. Funding: Multiple Sclerosis Society of the United Kingdom