Lung macrophage scavenger receptor SR-A6 (MARCO) is an adenovirus type-specific virus entry receptor

<div><p>Macrophages are a diverse group of phagocytic cells acting in host protection against stress, injury, and pathogens. Here, we show that the scavenger receptor SR-A6 is an entry receptor for human adenoviruses in murine alveolar macrophage-like MPI cells, and important for production of type I interferon. Scavenger receptors contribute to the clearance of endogenous proteins, lipoproteins and pathogens. Knockout of SR-A6 in MPI cells, anti-SR-A6 antibody or the soluble extracellular SR-A6 domain reduced adenovirus type-C5 (HAdV-C5) binding and transduction. Expression of murine SR-A6, and to a lower extent human SR-A6 boosted virion binding to human cells and transduction. Virion clustering by soluble SR-A6 and proximity localization with SR-A6 on MPI cells suggested direct adenovirus interaction with SR-A6. Deletion of the negatively charged hypervariable region 1 (HVR1) of hexon reduced HAdV-C5 binding and transduction, implying that the viral ligand for SR-A6 is hexon. SR-A6 facilitated macrophage entry of HAdV-B35 and HAdV-D26, two important vectors for transduction of hematopoietic cells and human vaccination. The study highlights the importance of scavenger receptors in innate immunity against human viruses.</p></div

Arrhythmogenic mechanisms of interleukin-6 combination with hydroxychloroquine and azithromycin in inflammatory diseases

Inflammatory diseases including COVID-19 are associated with a cytokine storm characterized by high interleukin-6 (IL-6) titers. In particular, while recent studies examined COVID-19 associated arrhythmic risks from cardiac injury and/or from pharmacotherapy such as the combination of azithromycin (AZM) and hydroxychloroquine (HCQ), the role of IL-6 per se in increasing the arrhythmic risk remains poorly understood. The objective is to elucidate the electrophysiological basis of inflammation-associated arrhythmic risk in the presence of AZM and HCQ. IL-6, AZM and HCQ were concomitantly administered to guinea pigs in-vivo and in-vitro. Electrocardiograms, action potentials and ion-currents were analyzed. IL-6 alone or the combination AZM + HCQ induced mild to moderate reduction in heart rate, PR-interval and corrected QT (QTc) in-vivo and in-vitro. Notably, IL-6 alone was more potent than the combination of the two drugs in reducing heart rate, increasing PR-interval and QTc. In addition, the in-vivo or in-vitro combination of IL-6 + AZM + HCQ caused severe bradycardia, conduction abnormalities, QTc prolongation and asystole. These electrocardiographic abnormalities were attenuated in-vivo by tocilizumab (TCZ), a monoclonal antibody against IL-6 receptor, and are due in part to the prolongation of action potential duration and selective inhibition of Na+, Ca2+ and K+ currents. Inflammation confers greater risk for arrhythmia than the drug combination therapy. As such, in the setting of elevated IL-6 during inflammation caution must be taken when co-administering drugs known to predispose to fatal arrhythmias and TCZ could be an important player as a novel anti-arrhythmic agent. Thus, identifying inflammation as a critical culprit is essential for proper management

Issues of geologically-focused situational awareness in robotic planetary missions: lessons from an analogue mission at Mistastin Lake impact structure, Labrador, Canada

Remote robotic data provides different information than that obtained from immersion in the field. This significantly affects the geological situational awareness experienced by members of a mission control science team. In order to optimize science return from planetary robotic missions, these limitations must be understood and their effects mitigated to fully leverage the field experience of scientists at mission control. Results from a 13-day analogue deployment at the Mistastin Lake impact structure in Labrador, Canada suggest that scale, relief, geological detail, and time are intertwined issues that impact the mission control science team‟s effectiveness in interpreting the geology of an area. These issues are evaluated and several mitigation options are suggested. Scale was found to be difficult to interpret without the reference of known objects, even when numerical scale data were available. For this reason, embedding intuitive scale-indicating features into image data is recommended. Since relief is not conveyed in 2D images, both 3D data and observations from multiple angles are required. Furthermore, the 3D data must be observed in animation or as anaglyphs, since without such assistance much of the relief information in 3D data is not communicated. Geological detail may also be missed due to the time required to collect, analyze, and request data. We also suggest that these issues can be addressed, in part, by an improved understanding of the operational time costs and benefits of scientific data collection. Robotic activities operate on inherently slow time-scales. This fact needs to be embraced and accommodated. Instead of focusing too quickly on the details of a target of interest, thereby potentially minimizing science return, time should be allocated at first to more broad data collection at that target, including preliminary surveys, multiple observations from various vantage points, and progressively smaller scale of focus. This operational model more closely follows techniques employed by field geologists and is fundamental to the geologic interpretation of an area. Even so, an operational time cost/benefit analyses should be carefully considered in each situation, to determine when such comprehensive data collection would maximize the science return. Finally, it should be recognized that analogue deployments cannot faithfully model the time scales of robotic planetary missions. Analogue missions are limited by the difficulty and expense of fieldwork. Thus, analogue deployments should focus on smaller aspects of robotic missions and test components in a modular way (e.g., dropping communications constraints, limiting mission scope, focusing on a specific problem, spreading the mission over several field seasons, etc.)

Patient-Reported Outcomes and Quality of Life Assessment. New Targets for New Targeted Therapy?

No abstract availabl

Transcriptional initiation and postinitiation effects of murine leukemia virus long terminal repeat R-region sequences

Sequences within the R components of the long terminal repeats (LTRs) of several retroviruses are known to be involved at various steps in expression of the viral genomes. A series of experiments was performed to test whether sequences within the R regions of the murine leukemia viruses Akv and SL3-3 affect viral expression. By using plasmid clones of the viral LTRs linked to a reporter gene, deletion of the R region was found to decrease expression to variable extents in a series of mammalian cell lines, with the largest effects being detected in murine fibroblasts. R-region sequences from the human immunodeficiency virus type 1 LTR or a random sequence were unable to substitute for the murine leukemia virus sequences. Transcripts from the R-region-deleted templates were initiated at the proper site in the LTR, but their levels were decreased at least 10-fold. Nuclear run-on assays showed that the decrease caused by the R-region deletions was due, in part, to an effect on RNA polymerase loading, suggesting an effect on transcriptional initiation. The remainder of the activity was presumably due to a posttranscriptional effect. Analysis of the R-region sequences of murine leukemia viruses and related retroviruses led to the prediction of a conserved secondary structure in the transcribed RNA that might have a role in activity. We conclude that R-region sequences are of importance for the expression of a variety of retroviruses.</jats:p