Dysregulated Choline, Methionine, and Aromatic Amino Acid Metabolism in Patients with Wilson Disease: Exploratory Metabolomic Profiling and Implications for Hepatic and Neurologic Phenotypes.

Wilson disease (WD) is a genetic copper overload condition characterized by hepatic and neuropsychiatric symptoms with a not well-understood pathogenesis. Dysregulated methionine cycle is reported in animal models of WD, though not verified in humans. Choline is essential for lipid and methionine metabolism. Defects in neurotransmitters as acetylcholine, and biogenic amines are reported in WD; however, less is known about their circulating precursors. We aimed to study choline, methionine, aromatic amino acids, and phospholipids in serum of WD subjects. Hydrophilic interaction chromatography-quadrupole time-of-flight mass spectrometry was employed to profile serum of WD subjects categorized as hepatic, neurologic, and pre-clinical. Hepatic transcript levels of genes related to choline and methionine metabolism were verified in the Jackson Laboratory toxic milk mouse model of WD (tx-j). Compared to healthy subjects, choline, methionine, ornithine, proline, phenylalanine, tyrosine, and histidine were significantly elevated in WD, with marked alterations in phosphatidylcholines and reductions in sphingosine-1-phosphate, sphingomyelins, and acylcarnitines. In tx-j mice, choline, methionine, and phosphatidylcholine were similarly dysregulated. Elevated choline is a hallmark dysregulation in WD interconnected with alterations in methionine and phospholipid metabolism, which are relevant to hepatic steatosis. The elevated phenylalanine, tyrosine, and histidine carry implications for neurologic manifestations and are worth further investigation

Microbial carbon use efficiency predicted from genome-scale metabolic models

Respiration by soil bacteria and fungi is one of the largest fluxes of carbon (C) from the land surface. Although this flux is a direct product of microbial metabolism, controls over metabolism and their responses to global change are a major uncertainty in the global C cycle. Here, we explore an in silico approach to predict bacterial C-use efficiency (CUE) for over 200 species using genome-specific constraint-based metabolic modeling. We find that potential CUE averages 0.62 ± 0.17 with a range of 0.22 to 0.98 across taxa and phylogenetic structuring at the subphylum levels. Potential CUE is negatively correlated with genome size, while taxa with larger genomes are able to access a wider variety of C substrates. Incorporating the range of CUE values reported here into a next-generation model of soil biogeochemistry suggests that these differences in physiology across microbial taxa can feed back on soil-C cycling.Published versio

Regulation-Structured Dynamic Metabolic Model Provides a Potential Mechanism for Delayed Enzyme Response in Denitrification Process

In a recent study of denitrification dynamics in hyporheic zone sediments, we observed a significant time lag (up to several days) in enzymatic response to the changes in substrate concentration. To explore an underlying mechanism and understand the interactive dynamics between enzymes and nutrients, we developed a trait-based model that associates a community’s traits with functional enzymes, instead of typically used species guilds (or functional guilds). This enzyme-based formulation allows to collectively describe biogeochemical functions of microbial communities without directly parameterizing the dynamics of species guilds, therefore being scalable to complex communities. As a key component of modeling, we accounted for microbial regulation occurring through transcriptional and translational processes, the dynamics of which was parameterized based on the temporal profiles of enzyme concentrations measured using a new signature peptide-based method. The simulation results using the resulting model showed several days of a time lag in enzymatic responses as observed in experiments. Further, the model showed that the delayed enzymatic reactions could be primarily controlled by transcriptional responses and that the dynamics of transcripts and enzymes are closely correlated. The developed model can serve as a useful tool for predicting biogeochemical processes in natural environments, either independently or through integration with hydrologic flow simulators

Systems biology analysis of drivers underlying hallmarks of cancer cell metabolism.

Malignant transformation is often accompanied by significant metabolic changes. To identify drivers underlying these changes, we calculated metabolic flux states for the NCI60 cell line collection and correlated the variance between metabolic states of these lines with their other properties. The analysis revealed a remarkably consistent structure underlying high flux metabolism. The three primary uptake pathways, glucose, glutamine and serine, are each characterized by three features: (1) metabolite uptake sufficient for the stoichiometric requirement to sustain observed growth, (2) overflow metabolism, which scales with excess nutrient uptake over the basal growth requirement, and (3) redox production, which also scales with nutrient uptake but greatly exceeds the requirement for growth. We discovered that resistance to chemotherapeutic drugs in these lines broadly correlates with the amount of glucose uptake. These results support an interpretation of the Warburg effect and glutamine addiction as features of a growth state that provides resistance to metabolic stress through excess redox and energy production. Furthermore, overflow metabolism observed may indicate that mitochondrial catabolic capacity is a key constraint setting an upper limit on the rate of cofactor production possible. These results provide a greater context within which the metabolic alterations in cancer can be understood

Ocean Worlds : May 21–23, 2018, Houston, Texas

The focus will be on the potential for silicate-water interactions to occur on Ocean Worlds beyond Earth, from a multi-disciplinary and inter-disciplinary perspective.Organizers Lunar and Planetary Institute, Universities Space Research Association ; Convener Louise Prockter, Lunar and Planetary Institute ; Science Organizing Committee Julie Castillo, NASA Jet Propulsion Laboratory, Christopher German, Wood Hole Oceanographic Institution, Jonathan Kay, Lunar and Planetary Institute, Marc Neveu, NASA Headquarters, Beth Orcutt, Bigelow Laboratory for Ocean Sciences, Paul Schenk, Lunar and Planetary Institute, Christophe Sotin, NASA Jet Propulsion Laboratory, Hajime Yano, Japan Aerospace Exploration Agency.PARTIAL CONTENTS: Geothermal Energy in Planetary Icy Large Objects via Cosmic Rays Muon–Catalyzed Fusion / A. de Morais -- The Fate of Electrons in Oceanic Alteration of Mid-Ocean Ridge Basalts / T. D. Ely and E. L. Shock -- Massive Hydrothermal Flows of Fluids and Heat: Earth Constraints and Ocean World Considerations / A. T. Fisher -- Compaction-Driven Evolution of Pluto’s Rocky Core: Implications for Water-Rock Interactions / L. R. Gabasova, G. Tobie, and G. Choblet -- Seafloor Fluid Flow and the Search for Extant Life: Escaping Earthly Prejudices / C. R. German -- Somewhere, Beyond the Sea: Advancing Geochemical Sensor Technologies for Biological and Abiotic Analyses on Ocean Worlds / P. R. Girguis, D. Hoer, A. Michel, S. D. Wankel, I. Baker, and N. Farr -- Interactions Between Ocean Circulation and Topography in Icy Worlds / J. C. Goodman -- Ocean Worlds of the Outer Solar System / K. P. Hand -- Faults and Fractures in the Subseafloor Environment tell a Different Story than They do at the Seafloor / N. W. Hayman

Peroxide impact on the fate of veterinary drugs in fertilizers

The presence of veterinary medicines in organic manure causes soil contamination which contributes to increasing resistance of indigenous microflora to drugs and results in greater susceptibility of people to allergies. The main aim of the study was to assess the efficiency of inorganic peroxide mixtures (PM) with calcium peroxide content (CaO2) in the stabilization process of manure contaminated with antiparasitic agents: albendazole (ALB) and levamisole (LEV). As a solid, CaO2 is relatively stable against decomposition. In contact with water, however, it hydrolyzes with release of oxygen. The hydrolyzation of CaO2 proceeds very slowly in soil, which guarantees the constant release of hydrogen peroxide that subsequently becomes the source of free radicals (chemical oxidation) and oxygen (aerobic conditions for the microbes). It may contribute to continuous elimination of drugs from manure. The study has demonstrated that there were significant differences in ALB and LEV conversion stimulated by the PM addition. PM supplementation increased the drug availability (on average 15% and 25% increase in the initial concentration for ALB and for LEV, respectively), thereby increasing the initial rate of reaction. Elimination of ALB and LEV from the manure sorption complex is followed by Ca2+ saturation. The initial degradation rate was affected by PM for both drugs, but the mechanisms of decomposition have been modified only for ALB. The loss of ALB in the peroxide supplemented samples was 92%, and in the samples, without the PM, it did not exceed 61%. Loss of LEV was over 90% irrespective of PM supplementation.Web of Science74132231

Adsorption and desorption dynamics of citric acid anions in soil

The functional role of organic acid anions (e.g. citrate, oxalate, malonate, etc) in soil has been intensively investigated with special focus either on (i) microbial respiration and soil carbon dynamics, (ii) nutrient solubilization, or (iii) metal detoxification. Considering the potential impact of sorption processes on the functional significance of these effects, comparatively little is known about the adsorption and desorption dynamics of organic acid anions in soils. The aim of this study therefore was to experimentally characterize the adsorption and desorption dynamics of organic acid anions in different soils using citrate as a model carboxylate. Results showed that both adsorption and desorption processes were fast, reaching a steady state equilibrium solution concentration within approximately 1 hour. However, for a given total soil citrate concentration(ctot) the steady state value obtained was critically dependent on the starting conditions of the experiment (i.e. whether most of the citrate was initially present in solution (cl) or held on the solid phase (cs)). Specifically, desorption-led processes resulted in significantly lower equilibrium solution concentrations than adsorption led processes indicating time-dependent sorption hysteresis. As it is not possible to experimentally distinguish between different sorption pools in soil (i.e. fast, slow, irreversible adsorption/desorption), a new dynamic hysteresis model was developed that relies only on measured soil solution concentrations. The model satisfactorily explained experimental data and was able to predict dynamic adsorption and desorption behaviour. To demonstrate its use we applied the model to two relevant scenarios (exudation and microbial degradation), where the dynamic sorption behaviour of citrate occurs. Overall, this study highlights the complex nature of citrate sorption in soil and concludes that existing models need to incorporate both a temporal and sorption hysteresis component to realistically describe the role and fate of organic acids in soil processes

Genome-driven evolutionary game theory helps understand the rise of metabolic interdependencies in microbial communities

Metabolite exchanges in microbial communities give rise to ecological interactions that govern ecosystem diversity and stability. It is unclear, however, how the rise of these interactions varies across metabolites and organisms. Here we address this question by integrating genome-scale models of metabolism with evolutionary game theory. Specifically, we use microbial fitness values estimated by metabolic models to infer evolutionarily stable interactions in multi-species microbial “games”. We first validate our approach using a well-characterized yeast cheater-cooperator system. We next perform over 80,000 in silico experiments to infer how metabolic interdependencies mediated by amino acid leakage in Escherichia coli vary across 189 amino acid pairs. While most pairs display shared patterns of inter-species interactions, multiple deviations are caused by pleiotropy and epistasis in metabolism. Furthermore, simulated invasion experiments reveal possible paths to obligate cross-feeding. Our study provides genomically driven insight into the rise of ecological interactions, with implications for microbiome research and synthetic ecology.We gratefully acknowledge funding from the Defense Advanced Research Projects Agency (Purchase Request No. HR0011515303, Contract No. HR0011-15-C-0091), the U.S. Department of Energy (Grants DE-SC0004962 and DE-SC0012627), the NIH (Grants 5R01DE024468 and R01GM121950), the national Science Foundation (Grants 1457695 and NSFOCE-BSF 1635070), MURI Grant W911NF-12-1-0390, the Human Frontiers Science Program (grant RGP0020/2016), and the Boston University Interdisciplinary Biomedical Research Office ARC grant on Systems Biology Approaches to Microbiome Research. We also thank Dr Kirill Korolev and members of the Segre Lab for their invaluable feedback on this work. (HR0011515303 - Defense Advanced Research Projects Agency; HR0011-15-C-0091 - Defense Advanced Research Projects Agency; DE-SC0004962 - U.S. Department of Energy; DE-SC0012627 - U.S. Department of Energy; 5R01DE024468 - NIH; R01GM121950 - NIH; 1457695 - national Science Foundation; NSFOCE-BSF 1635070 - national Science Foundation; W911NF-12-1-0390 - MURI; RGP0020/2016 - Human Frontiers Science Program; Boston University Interdisciplinary Biomedical Research Office ARC)Published versio