Dual GPCR and GAG mimicry by the M3 chemokine decoy receptor

Viruses have evolved a myriad of evasion strategies focused on undermining chemokine-mediated immune surveillance, exemplified by the mouse γ-herpesvirus 68 M3 decoy receptor. Crystal structures of M3 in complex with C chemokine ligand 1/lymphotactin and CC chemokine ligand 2/monocyte chemoattractant protein 1 reveal that invariant chemokine features associated with G protein–coupled receptor binding are primarily recognized by the decoy C-terminal domain, whereas the N-terminal domain (NTD) reconfigures to engage divergent basic residue clusters on the surface of chemokines. Favorable electrostatic forces dramatically enhance the association kinetics of chemokine binding by M3, with a primary role ascribed to acidic NTD regions that effectively mimic glycosaminoglycan interactions. Thus, M3 employs two distinct mechanisms of chemical imitation to potently sequester chemokines, thereby inhibiting chemokine receptor binding events as well as the formation of chemotactic gradients necessary for directed leukocyte trafficking

Marine Reserves and Reproductive Biomass: A Case Study of a Heavily Targeted Reef Fish

Recruitment overfishing (the reduction of a spawning stock past a point at which the stock can no longer replenish itself) is a common problem which can lead to a rapid and irreversible fishery collapse. Averting this disaster requires maintaining a sufficient spawning population to buffer stochastic fluctuations in recruitment of heavily harvested stocks. Optimal strategies for managing spawner biomass are well developed for temperate systems, yet remain uncertain for tropical fisheries, where the danger of collapse from recruitment overfishing looms largest. In this study, we explored empirically and through modeling, the role of marine reserves in maximizing spawner biomass of a heavily exploited reef fish, Lethrinus harak around Guam, Micronesia. On average, spawner biomass was 16 times higher inside the reserves compared with adjacent fished sites. Adult density and habitat-specific mean fish size were also significantly greater. We used these data in an age-structured population model to explore the effect of several management scenarios on L. harak demography. Under minimum-size limits, unlimited extraction and all rotational-closure scenarios, the model predicts that preferential mortality of larger and older fish prompt dramatic declines in spawner biomass and the proportion of male fish, as well as considerable declines in total abundance. For rotational closures this occurred because of the mismatch between the scales of recovery and extraction. Our results highlight how alternative management scenarios fall short in comparison to marine reserves in preserving reproductively viable fish populations on coral reefs

Recommended best practices for plastic and litter ingestion studies in marine birds: Collection, processing, and reporting

doi: 10.1139/facets-2018-0043Marine plastic pollution is an environmental contaminant of significant concern. There is a lack of consistency in sample collection and processing that continues to impede meta-analyses and largescale comparisons across time and space. This is true for most taxa, including seabirds, which are the most studied megafauna group with regards to plastic ingestion research. Consequently, it is difficult to evaluate the impacts and extent of plastic contamination in seabirds fully and accurately, and to make inferences about species for which we have little or no data. We provide a synthesized set of recommendations specific for seabirds and plastic ingestion studies that include best practices in relation to sample collection, processing, and reporting, as well as highlighting some “cross-cutting” methods. We include guidance for how carcasses, regurgitations, and pellets should be handled and treated to prevent cross-contamination, and a discussion of what size class of microplastics can be assessed in each sample type. Although we focus on marine bird samples, we also include standardized techniques to remove sediment and biological material that are generalizable to other taxa. Lastly, metrics and data presentation of ingested plastics are briefly reviewed in the context of seabird studies.Copyright: © 2019 Provencher et al. This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. The attached file is the published pdf

Calcified plaque modification alters local drug delivery in the treatment of peripheral atherosclerosis

Background: Calcific atherosclerosis is a major challenge to intraluminal drug delivery in peripheral artery disease (PAD). Objectives: We evaluated the effects of orbital atherectomy on intraluminal paclitaxel delivery to human peripheral arteries with substantial calcified plaque. Methods: Diagnostic angiography and 3-D rotational imaging of five fresh human lower limbs revealed calcification in all main arteries. The proximal or distal segment of each artery was treated using an orbital atherectomy system (OAS) under simulated blood flow and fluoroscopy. Explanted arterial segments underwent either histomorphometric assessment of effect or tracking of [superscript 14]C-labeled or fluorescent–labeled paclitaxel. Radiolabeled drug quantified bulk delivery and fluorescent label established penetration of drug over finer spatial domain in serial microscopic sections. Results: were interpreted using a mathematical model of binding-diffusion mediated arterial drug distribution. Results Lesion composition affected paclitaxel absorption and distribution in cadaveric human peripheral arteries. Pretreatment imaging calcium scores in control femoropopliteal arterial segments correlated with a log-linear decline in the bulk absorption rate-constant of [superscript 14]C-labeled, declining 5.5-fold per calcified quadrant (p = 0.05, n = 7). Compared to controls, OAS-treated femoropopliteal segments exhibited 180 μm thinner intima (p < 0.001), 45% less plaque calcification, and 2 log orders higher paclitaxel bulk absorption rate-constants. Correspondingly, fluorescent paclitaxel penetrated deeper in OAS-treated femoropopliteal segments compared to controls, due to a 70% increase in diffusivity (p < 0.001). Conclusions These data illustrate that calcified plaque limited intravascular drug delivery, and controlled OAS treatment of calcific plaques resulted in greater drug permeability and improved adjunct drug delivery to diseased arteries.Peripheral artery disease Keywords: Drug coated balloons, Drug eluting stents, Atherectomy, Orbital atherectomy, calcified plaque, PaclitaxelNational Institute of Mental Health (U.S.) (Grant R01 GM-49039

Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms

Genetic variations in the myeloid immune receptor TREM2 are linked to several neurodegenerative diseases. To determine how TREM2 variants contribute to these diseases, we performed structural and functional studies of wild-type and variant proteins. Our 3.1 Å TREM2 crystal structure revealed that mutations found in Nasu-Hakola disease are buried whereas Alzheimer’s disease risk variants are found on the surface, suggesting that these mutations have distinct effects on TREM2 function. Biophysical and cellular methods indicate that Nasu-Hakola mutations impact protein stability and decrease folded TREM2 surface expression, whereas Alzheimer’s risk variants impact binding to a TREM2 ligand. Additionally, the Alzheimer’s risk variants appear to epitope map a functional surface on TREM2 that is unique within the larger TREM family. These findings provide a guide to structural and functional differences among genetic variants of TREM2, indicating that therapies targeting the TREM2 pathway should be tailored to these genetic and functional differences with patient-specific medicine approaches for neurodegenerative disorders. DOI: http://dx.doi.org/10.7554/eLife.20391.00

Basal epithelial stem cells cross an alarmin checkpoint for postviral lung disease

Epithelial cells are charged with protection at barrier sites, but whether this normally beneficial response might sometimes become dysfunctional still needs definition. Here, we recognized a pattern of imbalance marked by basal epithelial cell growth and differentiation that replaced normal airspaces in a mouse model of progressive postviral lung disease due to the Sendai virus. Single-cell and lineage-tracing technologies identified a distinct subset of basal epithelial stem cells (basal ESCs) that extended into gas-exchange tissue to form long-term bronchiolar-alveolar remodeling regions. Moreover, this cell subset was selectively expanded by crossing a cell-growth and survival checkpoint linked to the nuclear-localized alarmin IL-33 that was independent of IL-33 receptor signaling and instead connected to autocrine chromatin accessibility. This mechanism creates an activated stem-progenitor cell lineage with potential for physiological or pathological function. Thus, conditional loss of Il33 gene function in basal epithelial cells disrupted the homeostasis of the epithelial barrier at skin and gut sites but also markedly attenuated postviral disease in the lung based on the downregulation of remodeling and inflammation. Thus, we define a basal ESC strategy to deploy innate immune machinery that appears to overshoot the primordial goal of self-defense. Our findings reveal new targets to stratify and correct chronic and often deadly postviral disease

Long-term IL-33-producing epithelial progenitor cells in chronic obstructive lung disease

Chronic obstructive lung disease is characterized by persistent abnormalities in epithelial and immune cell function that are driven, at least in part, by infection. Analysis of parainfluenza virus infection in mice revealed an unexpected role for innate immune cells in IL-13–dependent chronic lung disease, but the upstream driver for the immune axis in this model and in humans with similar disease was undefined. We demonstrate here that lung levels of IL-33 are selectively increased in postviral mice with chronic obstructive lung disease and in humans with very severe chronic obstructive pulmonary disease (COPD). In the mouse model, IL-33/IL-33 receptor signaling was required for Il13 and mucin gene expression, and Il33 gene expression was localized to a virus-induced subset of airway serous cells and a constitutive subset of alveolar type 2 cells that are both linked conventionally to progenitor function. In humans with COPD, IL33 gene expression was also associated with IL13 and mucin gene expression, and IL33 induction was traceable to a subset of airway basal cells with increased capacities for pluripotency and ATP-regulated release of IL-33. Together, these findings provide a paradigm for the role of the innate immune system in chronic disease based on the influence of long-term epithelial progenitor cells programmed for excess IL-33 production

Preliminary Numerical and Experimental Analysis of the Spallation Phenomenon

The spallation phenomenon was studied through numerical analysis using a coupled Lagrangian particle tracking code and a hypersonic aerothermodynamics computational fluid dynamics solver. The results show that carbon emission from spalled particles results in a significant modification of the gas composition of the post shock layer. Preliminary results from a test-campaign at the NASA Langley HYMETS facility are presented. Using an automated image processing of high-speed images, two-dimensional velocity vectors of the spalled particles were calculated. In a 30 second test at 100 W/cm2 of cold-wall heat-flux, more than 1300 particles were detected, with an average velocity of 102 m/s, and most frequent observed velocity of 60 m/s

Proteins in tumor-derived plasma extracellular vesicles indicate tumor origin

Cancer-derived extracellular vesicles (EVs) promote tumorigenesis, premetastatic niche formation, and metastasis via their protein cargo. However, the proteins packaged by patient tumors into EVs cannot be determined in vivo because of the presence of EVs derived from other tissues. We therefore developed a cross-species proteomic method to quantify the human tumor-derived proteome of plasma EVs produced by patient-derived xenografts of four cancer types. Proteomic profiling revealed individualized packaging of novel protein cargo, and machine learning accurately classified the type of the underlying tumor