MicroRNA-146a is upregulated by and negatively regulates TLR2 signaling

TLR signaling is a crucial component of the innate immune response to infection. MicroRNAs (miRNAs) have been shown to be upregulated during TLR signaling. Specifically, microRNA-146a (miR-146a) plays a key role in endotoxin tolerance by downregulating interleukin-1 receptor-associated kinase 1 (IRAK-1). The aim of this study was to assess the role of miR-146a in the TLR2 signaling and development of bacterial lipoprotein (BLP) self-tolerance and cross-tolerance to bacteria. Expression of miR-146a increased in a dose- and time-dependent manner in BLP-stimulated human THP-1 promonocytic cells. In BLP-tolerised cells miR-146a was even further upregulated in response to BLP re-stimulation (p,0.001). Restimulation of BLP-tolerised cells with heat-killed gram-negative Salmonella typhimurium (S. typhimurium), but not grampositive Staphylococcus aureus (S. aureus), led to significant overexpression of miR-146a (p,0.05). Transfection of naive cells with a miR-146a mimic substantially suppressed TNF-a production (p,0.05). Furthermore, overexpression of miR-146a resulted in strong reduction in IRAK-1 and phosphorylated IkBa expression in naive and S. typhimurium-stimulated THP-1 cells. Collectively, miR-146a is upregulated in response to BLP and bacterial stimulation in both naive and BLP-tolerised cells. Overexpression of miR-146a induces a state analogous to tolerance in BLP-stimulated cells and therefore may represent a future target for exogenous modulation of tolerance during microbial infection and sepsi

Synchronized Optical and Electronic Detection of Biomolecules Using a Low Noise Nanopore Platform

In the past two decades there has been a tremendous amount of research into the use of nanopores as single molecule sensors, which has been inspired by the Coulter counter and molecular transport across biological pores. Recently, the desire to increase structural resolution and analytical throughput has led to the integration of additional detection methods such as fluorescence spectroscopy. For structural information to be probed electronically high bandwidth measurements are crucial due to the high translocation velocity of molecules. The most commonly used solid-state nanopore sensors consist of a silicon nitride membrane and bulk silicon substrate. Unfortunately, the photoinduced noise associated with illumination of these platforms limits their applicability to high-bandwidth, high-laser-power synchronized optical and electronic measurements. Here we present a unique low-noise nanopore platform, composed of a predominately Pyrex substrate and silicon nitride membrane, for synchronized optical and electronic detection of biomolecules. Proof of principle experiments are conducted showing that the Pyrex substrates have substantially lowers ionic current noise arising from both laser illumination and platform capacitance. Furthermore, using confocal microscopy and a partially metallic pore we demonstrate high signal-to-noise synchronized optical and electronic detection of dsDNA

Reviews may overestimate the effectiveness of medicines for back pain: Systematic review and meta-analysis

Objective: Systematic-reviews of analgesics for low back pain generally include published data only. Obtaining data from unpublished trials is potentially important because they may impact effect sizes in meta-analyses. We determined whether including unpublished data from trial registries changes the effect sizes in meta-analyses of analgesics for low back pain. Study Design and Setting: Trial registries were searched for unpublished data that conformed to the inclusion criteria of n=5 individual source systematic-reviews. We reproduced the meta-analyses using data available from the original reviews then re-ran the same analyses with the addition of new unpublished data. Results: Sixteen completed, unpublished, trials were eligible for inclusion in four of the source reviews. Data were available for five trials. We updated the analyses for two of the source reviews. The addition of data from two trials reduced the effect size of muscle relaxants, compared to sham, for recent-onset low back pain from -21.71 (95%CI -28.23 to -15.19) to -2.34 (95%CI -3.34 to -1.34) on a 0-100 scale for pain intensity. The addition of data from three trials (one enriched design) reduced the effect size of opioid analgesics, compared to sham, for chronic low back pain from -10.10 (95%CI -12.81 to -7.39) to -9.31 (95%CI -11.51 to -7.11). The effect reduced in the subgroup of enriched design studies, from -12.40 (95%CI -16.90 to -7.91) to 11.34 (95%CI -15.36 to -7.32), and in the subgroup of non-enriched design studies; from -7.27 (95%CI -9.97 to -4.57) to -7.19 (95%CI -9.24 to -5.14). Conclusion: Systematic-reviews should include reports of unpublished trials. The result for muscle relaxants conflicts with the conclusion of the published review and recent international guidelines. Adding unpublished data strengthens the evidence that opioid analgesics have small effects on persistent low back pain and more clearly suggests these effects may not be clinically meaningful

Systematic reviews that include only published data may overestimate the effectiveness of analgesic medicines for low back pain: A systematic review and meta-analysis

Objective: Systematic reviews of analgesics for low back pain generally include published data only. Obtaining data from unpublished trials is potentially important because they may impact effect sizes in meta-analyses. We determined whether including unpublished data from trial registries changes the effect sizes in meta-analyses of analgesics for low back pain. Study Design and Setting: Trial registries were searched for unpublished data that conformed to the inclusion criteria of n = 5 individual source systematic reviews. We reproduced the meta-analyses using data available from the original reviews and then reran the same analyses with the addition of new unpublished data. Results: Sixteen completed, unpublished, trials were eligible for inclusion in four of the source reviews. Data were available for five trials. We updated the analyses for two of the source reviews. The addition of data from two trials reduced the effect size of muscle relaxants, compared with sham, for recent-onset low back pain from −21.71 (95% CI: −28.23 to −15.19) to −2.34 (95% CI: −3.34 to −1.34) on a 0–100 scale for pain intensity. The addition of data from three trials (one enriched design) reduced the effect size of opioid analgesics, compared with sham, for chronic low back pain from −10.10 (95% CI: −12.81 to −7.39) to −9.31 (95% CI: −11.51 to −7.11). The effect reduced in the subgroup of enriched design studies, from −12.40 (95% CI: −16.90 to −7.91) to −11.34 (95% CI: −15.36 to −7.32), and in the subgroup of nonenriched design studies, from −7.27 (95% CI: −9.97 to −4.57) to −7.19 (95% CI: −9.24 to −5.14). Conclusion: Systematic reviews should include reports of unpublished trials. The result for muscle relaxants conflicts with the conclusion of the published review and recent international guidelines. Adding unpublished data strengthens the evidence that opioid analgesics have small effects on persistent low back pain and more clearly suggests these effects may not be clinically meaningful

The impact of routine open nonsuction drainage on fluid accumulation after thyroid surgery: a prospective randomised clinical trial.

Background: Thyroid drains following thyroid surgery are routinely used despite minimal supportive evidence. Our aim in this study is to determine the impact of routine open drainage of the thyroid bed postoperatively on ultrasound-determined fluid accumulation at 24 hours. Methods: We conducted a prospective randomised clinical trial on patients undergoing thyroid surgery. Patients were randomly assigned to a drain group (n = 49) or a no-drain group (n = 44) immediately prior to wound closure. Patients underwent a neck ultrasound on day 1 and day 2 postoperatively. After surgery, we evaluated visual analogue scale pain scores, postoperative analgesic requirements, self-reported scar satisfaction at 6 weeks and complications. Results: There was significantly less mean fluid accumulated in the drain group on both day 1, 16.4 versus 25.1 ml (P-value = 0.005), and day 2, 18.4 versus 25.7 ml (P-value = 0.026), following surgery. We found no significant differences between the groups with regard to length of stay, scar satisfaction, visual analogue scale pain score and analgesic requirements. There were four versus one wound infections in the drain versus no-drain groups. This finding was not statistically significant (P = 0.154). No life-threatening bleeds occurred in either group. Conclusions: Fluid accumulation after thyroid surgery was significantly lessened by drainage. However, this study did not show any clinical benefit associated with this finding in the non-emergent setting. Drains themselves showed a trend indicating that they may augment infection rates. The results of this study suggest that the frequency of acute life-threatening bleeds remains extremely low following abandoning drains. We advocate abandoning routine use of thyroid drains. Trial registration: ISRCTN94715414

It\u27s safe to move! A protocol for a randomised controlled trial investigating the effect of a video designed to increase people\u27s confidence becoming more active despite back pain

Introduction Social media provide promising contemporary platforms for sharing public health information with a broad audience. Before implementation, testing social media campaigns that are intended to engage audiences and initiate behaviour change is necessary. This trial aims to investigate the effectiveness of a public health campaign to increase people\u27s confidence in becoming more active despite low back pain in comparison with no intervention. Methods and analysis This is an online randomised controlled trial with two intervention groups and one control group in a 1:1:1 allocation. People over 18 years of age and fluent in English will be recruited via social media advertising. We developed a social media-based public health campaign to support recommendations for managing low back pain. The interventions are two videos. Participants in the control group will be asked questions about low back pain but will not view either video intervention. The primary outcome will be item 10 of the Pain Self-Efficacy Questionnaire, which asks participants to rate how confident they would feel to gradually become more active despite pain ranging from 0 (not at all confident) to 6 (completely confident). This outcome will be measured immediately in all participant groups. We will compare group mean of the three arms of the trial using univariate analyses of variance. Ethics and dissemination This trial has been prospectively registered with the Australian New Zealand Clinical Trials Registry. We obtained ethical approval from our institutions Human Research Ethics Committee before data collection. We will publish the results in a peer-reviewed medical journal and on institution websites

Metatranscriptomic Comparison of Endophytic and Pathogenic \u3cem\u3eFusarium\u3c/em\u3e-Arabidopsis Interactions Reveals Plant Transcriptional Plasticity

Plants are continuously exposed to beneficial and pathogenic microbes, but how plants recognize and respond to friends versus foes remains poorly understood. Here, we compared the molecular response of Arabidopsis thaliana independently challenged with a Fusarium oxysporum endophyte Fo47 versus a pathogen Fo5176. These two F. oxysporum strains share a core genome of about 46 Mb, in addition to 1,229 and 5,415 unique accessory genes. Metatranscriptomic data reveal a shared pattern of expression for most plant genes (about 80%) in responding to both fungal inoculums at all timepoints from 12 to 96 h postinoculation (HPI). However, the distinct responding genes depict transcriptional plasticity, as the pathogenic interaction activates plant stress responses and suppresses functions related to plant growth and development, while the endophytic interaction attenuates host immunity but activates plant nitrogen assimilation. The differences in reprogramming of the plant transcriptome are most obvious in 12 HPI, the earliest timepoint sampled, and are linked to accessory genes in both fungal genomes. Collectively, our results indicate that the A. thaliana and F. oxysporum interaction displays both transcriptome conservation and plasticity in the early stages of infection, providing insights into the fine-tuning of gene regulation underlying plant differential responses to fungal endophytes and pathogens

A Novel Closed-Head Model of Mild Traumatic Brain Injury Caused by Primary Overpressure Blast to the Cranium Produces Sustained Emotional Deficits in Mice

Emotional disorders are a common outcome from mild traumatic brain injury (TBI) in humans, but their pathophysiological basis is poorly understood. We have developed a mouse model of closed-head blast injury using an air pressure wave delivered to a small area on one side of the cranium, to create mild TBI. We found that 20-psi blasts in 3-month-old C57BL/6 male mice yielded no obvious behavioral or histological evidence of brain injury, while 25–40 psi blasts produced transient anxiety in an open field arena but little histological evidence of brain damage. By contrast, 50–60 psi blasts resulted in anxiety-like behavior in an open field arena that became more evident with time after blast. In additional behavioral tests conducted 2–8 weeks after blast, 50–60 psi mice also demonstrated increased acoustic startle, perseverance of learned fear, and enhanced contextual fear, as well as depression-like behavior and diminished prepulse inhibition. We found no evident cerebral pathology, but did observe scattered axonal degeneration in brain sections from 50 to 60 psi mice 3–8 weeks after blast. Thus, the TBI caused by single 50–60 psi blasts in mice exhibits the minimal neuronal loss coupled to “diffuse” axonal injury characteristic of human mild TBI. A reduction in the abundance of a subpopulation of excitatory projection neurons in basolateral amygdala enriched in Thy1 was, however, observed. The reported link of this neuronal population to fear suppression suggests their damage by mild TBI may contribute to the heightened anxiety and fearfulness observed after blast in our mice. Our overpressure air blast model of concussion in mice will enable further studies of the mechanisms underlying the diverse emotional deficits seen after mild TBI

Quasi-free π0\pi^0 Photoproduction from the Bound Nucleon

Differential cross-sections for quasi-free $\pi^0$ photoproduction from the proton and neutron bound in the deuteron have been measured for $E_\gamma= 200 - 400$ MeV at $\theta^{\rm lab}_\gamma = 136.2^\circ$ usind the Glasgow photon tagger at MAMI, the Mainz 48 cm $\varnothing$ $\times$ 64 cm NaI(Tl) photon detector and the G\"ottingen SENECA recoil detector. For the proton measurements made with both liquid deuterium and liquid hydrogen targets allow direct comparison of "free" $\pi^0$ photoproduction cross-sections as extracted from the bound proton data with experimental free cross sections which are found to be in reasonable agreement below 320 MeV. At higher energies the "free" cross sections extracted from quasifree data are significantly smaller than the experimental free cross sections and theoretical predictions based on multipole analysis. For the first time, "free" neutron cross sections have been extracted in the $\Delta$-region. They are also in agreement with the predictions from multipole analysis up to 320 MeV and significantly smaller at higher photon energies