Metabolomic Characterization of Human Model of Liver Rejection Identifies Aberrancies Linked to Cyclooxygenase (COX) and Nitric Oxide Synthase (NOS)

BACKGROUND Acute liver rejection (ALR), a significant complication of liver transplantation, burdens patients, healthcare payers, and the healthcare providers due to an increase in morbidity, cost, and resources. Despite clinical resolution, ALR is associated with an increased risk of graft loss. A unique protocol of delayed immunosuppression used in our institute provided a model to characterize metabolomic profiles in human ALR. MATERIAL AND METHODS Twenty liver allograft biopsies obtained 48 hours after liver transplantation in the absence of immunosuppression were studied. Hepatic metabolites were quantitated in these biopsies by liquid chromatography and mass spectroscopy (LC/MS). Metabolite profiles were compared among: 1) biopsies with reperfusion injury but no histological evidence of rejection (n=7), 2) biopsies with histological evidence of moderate or severe rejection (n=5), and 3) biopsies with histological evidence of mild rejection (n=8). RESULTS There were 133 metabolites consistently detected by LC/MS and these were prioritized using variable importance to projection (VIP) analysis, comparing moderate or severe rejection vs. no rejection or mild rejection using partial least squares discriminant statistical analysis (PLS-DA). Twenty metabolites were identified as progressively different. Further PLS-DA using these metabolites identified 3 metabolites (linoleic acid, γ-linolenic acid, and citrulline) which are associated with either cyclooxygenase or nitric oxide synthase functionality. CONCLUSIONS Hepatic metabolic aberrancies associated with cyclooxygenase and nitric oxide synthase function occur contemporaneous with ALR. Additional studies are required to better characterize the role of these metabolic pathways to enhance utility of the metabolomics approach in diagnosis and outcomes of ALR

Integrated multi-trophic aquaculture mitigates the effects of ocean acidification: Seaweeds raise system pH and improve growth of juvenile abalone

Integrated multi-trophic aquaculture (IMTA) has the potential to enhance growth, reduce nutrient loads, and mitigate environmental conditions compared to traditional single-species culture techniques. The goal of this project was to develop a land-based system for the integrated culture of seaweeds and shellfish, to test the efficacy of integrated versus non-integrated designs, and to assess the potential for IMTA to mitigate the effects of climate change from ocean acidification on shellfish growth and physiology. We utilized the red abalone (Haliotis rufescens) and the red seaweed dulse (Devaleraea mollis) as our study species and designed integrated tanks at three different recirculation rates (0%, 30%, and 65% recirculation per hour) to test how an integrated design would affect growth rates of the abalone and seaweeds, modify nutrient levels, and change water chemistry. We specifically hypothesized that IMTA designs would raise seawater pH to benefit calcifying species. Our results indicated that juvenile abalone grew significantly faster in weight (22% increase) and shell area (11% increase) in 6 months in tanks with the highest recirculation rates (65%). The 65% recirculation treatment also exhibited a significant increase in mean seawater pH (0.2 pH units higher) due to the biological activity of the seaweed in the connected tanks. We found a significant positive relationship between the mean pH of seawater in the tanks and juvenile abalone growth rates across all treatments. There were no significant differences in the growth of dulse among treatments, but dulse growth did vary seasonally. Seawater phosphate and nitrate concentrations were depleted in the highest recirculation rate treatment, but ammonium concentrations were elevated, likely due to the abalone effluent. Overall, our results indicate that there are benefits to IMTA culture of seaweeds and abalone in terms of improving growth in land-based systems, which will reduce the time to market and buffer commercial abalone operations against the effects of ocean acidification during vulnerable early life stages

Interferon-stimulated gene (ISG)-expression screening reveals the specific antibunyaviral activity of ISG20

Bunyaviruses pose a significant threat to human health, prosperity and food security. In response to viral infections, interferons (IFNs) upregulate the expression of hundreds of interferon stimulated genes (ISGs) whose cumulative action can potently inhibit the replication of bunyaviruses. We used a flow cytometry-based method to screen the ability of ∼500 unique ISGs from humans and rhesus macaques to inhibit the replication of Bunyamwera orthobunyavirus (BUNV), the prototype of both the Peribunyaviridae family and Bunyavirales order. Candidates possessing antibunyaviral activity were further examined using a panel of divergent bunyaviruses. Interestingly, one candidate, ISG20, exhibited potent antibunyaviral activity against most viruses examined from the Peribunyaviridae, Hantaviridae and Nairoviridae families, whereas phleboviruses (Phenuiviridae) largely escaped inhibition. Similar to other viruses known to be targeted by ISG20, the antibunyaviral activity of ISG20 is dependent upon its functional ribonuclease activity. Through use of an infectious VLP assay (based on the BUNV minigenome system), we confirmed that gene expression from all 3 viral segments is strongly inhibited by ISG20. Using in vitro evolution, we generated a substantially ISG20-resistant BUNV and mapped the determinants of ISG20 sensitivity/resistance. Taken together, we report that ISG20 is a broad and potent antibunyaviral factor yet some bunyaviruses are remarkably ISG20 resistant. Thus, ISG20 sensitivity/resistance could influence the pathogenesis of bunyaviruses, many of which are emerging viruses of clinical or veterinary significance

Mucin binding reduces colistin antimicrobial activity

Colistin has found increasing use in treating drug-resistant bacterial lung infections, but potential interactions with pulmonary biomolecules have not been investigated. We postulated that colistin, like aminoglycoside antibiotics, may bind to secretory mucin in sputum or epithelial mucin that lines airways, reducing free drug levels. To test this hypothesis, we measured binding of colistin and other antibiotics to porcine mucin, a family of densely glycosylated proteins used as a surrogate for human sputum and airway mucin. Antibiotics were incubated in dialysis tubing with or without mucin, and concentrations of unbound antibiotics able to penetrate the dialysis tubing were measured over time using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The percentage of antibiotic measured in the dialysate after 4 h in the presence of mucin, relative to the amount without mucin, was 15% for colistin, 16% for polymyxin B, 19% for tobramycin, 52% for ciprofloxacin, and 78% for daptomycin. Antibiotics with the strongest mucin binding had an overall polybasic positive charge, whereas those with comparatively little binding were less basic. When comparing MICs measured with or without added mucin, colistin and polymyxin B showed >100-fold increases in MICs for multiple Gram-negative bacteria. Preclinical evaluation of mucin binding should become a standard procedure when considering the potential pulmonary use of new or existing antibiotics, particularly those with a polybasic overall charge. In the airways, mucin binding may reduce the antibacterial efficacy of inhaled or intravenously administered colistin, and the presence of sub-MIC effective antibiotic concentrations could result in the development of antibiotic resistance

Relativistic MHD with Adaptive Mesh Refinement

This paper presents a new computer code to solve the general relativistic magnetohydrodynamics (GRMHD) equations using distributed parallel adaptive mesh refinement (AMR). The fluid equations are solved using a finite difference Convex ENO method (CENO) in 3+1 dimensions, and the AMR is Berger-Oliger. Hyperbolic divergence cleaning is used to control the $\nabla\cdot {\bf B}=0$ constraint. We present results from three flat space tests, and examine the accretion of a fluid onto a Schwarzschild black hole, reproducing the Michel solution. The AMR simulations substantially improve performance while reproducing the resolution equivalent unigrid simulation results. Finally, we discuss strong scaling results for parallel unigrid and AMR runs.Comment: 24 pages, 14 figures, 3 table

Quantifying the Relationship between Capability and Health in Older People: Can't Map, Won't Map

BACKGROUND: Intuitively, health and capability are distinct but linked concepts. This study aimed to quantify the link between a measure of health status (EQ-5D-3L) and capability (ICECAP-O) using regression-based methods. METHODS: EQ-5D-3L and ICECAP-O data were collected from a sample of older people ( n = 584), aged over 65 years, requiring a hospital visit and/or care home resident, and recruited to one of 3 studies forming the Medical Crisis in Older People (MCOP) program in England. The link of EQ-5D-3L with 1) ICECAP-O tariff scores were estimated using ordinary least squares (OLS) or censored least absolute deviation (CLAD) regression models; and 2) ICECAP-O domain scores was estimated using multinomial logistic (MNL) regression. Mean absolute error (MAE), root mean squared error (RMSE), absolute difference (AD) between mean observed and estimated values, and the R(2) statistic were used to judge model performance. RESULTS: In this sample of older people ( n = 584), higher scores on the EQ-5D-3L were shown to be linked with higher ICECAP-O scores when using linear regression. An OLS-regression model was identified to be the best performing model with the lowest error statistics (AD = 0.0000; MAE = 0.1208; MSE = 0.1626) and highest goodness of fit ( R(2) = 0.3532); model performance was poor when predicting the lower ICECAP-O tariff scores. The three domains of the EQ-5D-3L showing a statistically significant quantifiable link with the ICECAP-O tariff score were self-care, usual activities, and anxiety/depression. CONCLUSION: A quantifiable, but weak, link between health (EQ-5D-3L) and capability (ICECAP-O) was identified. The findings from this study add further support that the ICECAP-O is providing complimentary information to the EQ-5D-3L. Mapping between the 2 measures is not advisable and the measures should not be used as direct substitutes to capture the impact of interventions in economic evaluations

Tracing molybdenum attenuation in mining environments using molybdenum stable isotopes

Molybdenum contamination is a concern in mining regions worldwide. Better understanding of processes controlling Mo mobility in mine wastes is critical for assessing potential impacts and developing water-quality management strategies associated to this element. Here, we used Mo stable isotope (δ98/95Mo) analyses to investigate geochemical controls on Mo mobility within a tailings management facility (TMF) featuring oxic and anoxic environments. These isotopic analyses were integrated with X-ray absorption spectroscopy, X-ray diffraction, Raman spectroscopy, transmission electron microscopy, and aqueous chemical data. Dissolved Mo concentrations were inversely correlated with δ98/95Mo values such that enrichment of heavy Mo isotopes in solution reflected attenuation processes. Inner-sphere complexation of Mo(VI) with ferrihydrite was the primary driver of Mo removal and was accompanied by a circa 1 ‰ isotope fractionation. Limited Mo attenuation and isotope fractionation was observed in Fe(II)- and Mo-rich anoxic TMF seepage, while attenuation and isotope fractionation were greatest during discharge and oxidation of this seepage after discharge into a pond where Fe-(oxyhydr)oxide precipitation promoted Mo sorption. Overall, this study highlights the role of sorption onto Fe-(oxyhydr)oxides in attenuating Mo in oxic environments, a process which can be traced by Mo isotope analyses

A Methodology for Successful University Graduate CubeSat Programs

The University of Colorado Smead Department of Aerospace Engineering has over a decade of success in designing, building, and operating student led CubeSat missions. The experience and lessons learned from building and operating the CSSWE, MinXSS-1, MinXSS-2, and QB50-Challenger missions have helped grow a knowledge base on the most effective and efficient ways to manage some of the “tall poles” when it comes to student run CubeSat missions. Among these “tall poles” we have seen student turnover, software, and documentation become some of the hardest to knock-down and we present our strategies for doing so. We use the MAXWELL mission (expected to launch in 2021) as a road-map to detail the methodology we have built over the last decade to ensure the greatest chance of mission success