Benchmark Concentrations for Untargeted Metabolomics Versus Transcriptomics for Liver Injury Compounds in In Vitro Liver Models.

Interpretation of untargeted metabolomics data from both in vivo and physiologically relevant in vitro model systems continues to be a significant challenge for toxicology research. Potency-based modeling of toxicological responses has served as a pillar of interpretive context and translation of testing data. In this study, we leverage the resolving power of concentration-response modeling through benchmark concentration (BMC) analysis to interpret untargeted metabolomics data from differentiated cultures of HepaRG cells exposed to a panel of reference compounds and integrate data in a potency-aligned framework with matched transcriptomic data. For this work, we characterized biological responses to classical human liver injury compounds and comparator compounds, known to not cause liver injury in humans, at 10 exposure concentrations in spent culture media by untargeted liquid chromatography-mass spectrometry analysis. The analyte features observed (with limited metabolites identified) were analyzed using BMC modeling to derive compound-induced points of departure. The results revealed liver injury compounds produced concentration-related increases in metabolomic response compared to those rarely associated with liver injury (ie, sucrose, potassium chloride). Moreover, the distributions of altered metabolomic features were largely comparable with those observed using high throughput transcriptomics, which were further extended to investigate the potential for in vitro observed biological responses to be observed in humans with exposures at therapeutic doses. These results demonstrate the utility of BMC modeling of untargeted metabolomics data as a sensitive and quantitative indicator of human liver injury potential.

Anaerobic Soil Disinfestation Efficacy Against Fusarium oxysporum Is Affected by Soil Temperature, Amendment Type, Rate, and C:N Ratio.

A meta-analysis of anaerobic soil disinfestation (ASD) efficacy against Fusarium oxysporum and F. oxysporum f. sp. lycopersici was conducted emphasizing effects of environment and organic amendment characteristics and pot and field studies conducted on ASD amendment C:N ratio and soil temperature effects on F. oxysporum f. sp. lycopersici inoculum survival. In a pot study, two organic amendments, dry molasses-based or wheat bran-based, applied at 4 mg of C/g of soil, with 40:1, 30:1, 20:1, and 10:1 C:N ratios, were evaluated against F. oxysporum f. sp. lycopersici at 15 to 25°C. This study was followed by a pot study with temperature regimes of 15 to 25°C and 25 to 35°C and two C:N ratios (20:1 and 40:1), and a field study at 40:1, 30:1, 20:1, and 10:1 C:N ratios, a 30:1 C:N ratio at a lower C rate (2 mg of C/g of soil), and an anaerobic control. Soil temperature >25°C and more labile amendments increased ASD suppression of F. oxysporum/F. oxysporum f. sp. lycopersici in the meta-analysis. In pot studies, F. oxysporum f. sp. lycopersici survival was reduced for molasses-based mixtures at 20:1 and 30:1 C:N ratios compared with wheat bran-based mixtures but not compared with the anaerobic control. At 25 to 35°C, all ASD treatments suppressed F. oxysporum f. sp. lycopersici relative to controls. In the field, all ASD treatments reduced F. oxysporum f. sp. lycopersici survival compared with the anaerobic control, and 4 mg of C/g of soil amendment rates induced higher anaerobic conditions and higher F. oxysporum f. sp. lycopersici mortality compared with the 2 mg of C/g of soil rate. Although amendment C:N ratios from 10 to 40:1 were similarly suppressive of F. oxysporum, lower temperatures reduced ASD effectiveness against F. oxysporum/F. oxysporum f. sp. lycopersici and further work is warranted to enhance suppression at soil temperatures <25°C.

Evaluation of 5-day In Vivo Rat Liver and Kidney With High-throughput Transcriptomics for Estimating Benchmark Doses of Apical Outcomes.

A 5-day in vivo rat model was evaluated as an approach to estimate chemical exposures that may pose minimal risk by comparing benchmark dose (BMD) values for transcriptional changes in the liver and kidney to BMD values for toxicological endpoints from traditional toxicity studies. Eighteen chemicals, most having been tested by the National Toxicology Program in 2-year bioassays, were evaluated. Some of these chemicals are potent hepatotoxicants (eg, DE71, PFOA, and furan) in rodents, some exhibit toxicity but have minimal hepatic effects (eg, acrylamide and α,ß-thujone), and some exhibit little overt toxicity (eg, ginseng and milk thistle extract) based on traditional toxicological evaluations. Male Sprague Dawley rats were exposed once daily for 5 consecutive days by oral gavage to 8-10 dose levels for each chemical. Liver and kidney were collected 24 h after the final exposure and total RNA was assayed using high-throughput transcriptomics (HTT) with the rat S1500+ platform. HTT data were analyzed using BMD Express 2 to determine transcriptional gene set BMD values. BMDS was used to determine BMD values for histopathological effects from chronic or subchronic toxicity studies. For many of the chemicals, the lowest transcriptional BMDs from the 5-day assays were within a factor of 5 of the lowest histopathological BMDs from the toxicity studies. These data suggest that using HTT in a 5-day in vivo rat model provides reasonable estimates of BMD values for traditional apical endpoints. This approach may be useful to prioritize chemicals for further testing while providing actionable data in a timely and cost-effective manner.

Sustainable fuel, food, fertilizer and ecosystems through a global artificial photosynthetic system: overcoming anticompetitive barriers.

This article discusses challenges that artificial photosynthetic (AP) systems will face when entering and competing in a global market characterized by established fossil fuel technology. It provides a perspective on the neoliberal principles underpinning much policy entrenching such environmentally destructive technology and outlines how competition law could aid overcoming these hurdles for AP development. In particular, it critiques the potential for competition law to promote a global AP initiative with greater emphasis on atmospheric carbon dioxide and nitrogen fixation (as well as solar-driven water splitting) to produce an equitable, globally distributed source of human food, fertilizer and biosphere sustainability, as well as hydrogen-based fuel. Some relevant strategies of competition law evaluated in this context include greater citizen-consumer involvement in shaping market values, legal requirements to factor services from the natural environment (i.e. provision of clean air, water, soil pollution degradation) into corporate costs, reform of corporate taxation and requirements to balance maximization of shareholder profit with contribution to a nominated public good, a global financial transactions tax, as well as prohibiting horizontal cartels, vertical agreements and unilateral misuse of market power.

Rational interface design of epoxy-organoclay nanocomposites: role of structure-property relationship for silane modifiers.

Montmorillonite was modified by three silane surfactants with different functionalities to investigate the role of surfactant structure on the properties of a final epoxy-organoclay nanocomposite. N-aminopropyldimethylethoxysilane (APDMES), an aminated monofunctional silane, was chosen as a promising surfactant for several reasons: (1) it will bond to silica in montmorillonite, (2) it will bond to epoxide groups, and (3) to overcome difficulties found with trifunctional aminosilane bonding clay layers together and preventing exfoliation. A trifunctional and non-aminated version of APDMES, 3-aminopropyltriethoxysilane (APTES) and n-propyldimethylmethoxysilane (PDMMS), respectively, was also studied to provide comparison to this rationally chosen surfactant. APDMES and APTES were grafted onto montmorillonite in the same amount, while PDMMS was barely grafted (<1 wt%). The gallery spacing of APDMES organoclay was greater than APTES or PDMMS, but the final nanocomposite gallery spacing was not dependent on the surfactant used. Different concentrations of APDMES modified montmorillonite yielded different properties, as concentration decreased glass transition temperature increased, thermal stability increased, and the storage modulus decreased. Storage modulus, glass transition temperature, and thermal stability were more similar for epoxy-organoclay composites modified with the same concentration of silane surfactant, neat epoxy, and epoxy-montmorillonite nanocomposite.

Planetary medicine and the Waitangi Tribunal Whanganui River report: global health law embracing ecosystem as patients.

A recent decision of the Waitangi Tribunal granted legal personhood to New Zealand's Whanganui River (appointing guardians to act in its interests). Exploring the impacts of this decision, this column argues that new technologies (such as artificial photosynthesis) may soon be creating policy opportunities not only for legal personhood to be stripped from some artificial persons, but for components of the natural world (such as rivers and other ecosystems) to be granted such enforceable legal rights. Such technologies, if deployed globally, may do this by taking the pressure off ecosystems to be exploited for human profit and survival. It argues that, by also creating normative space for such an expansion of sympathy, global heath law begins to incorporate the vision of planet as patient.

Nerve growth factor potentiates p53 DNA binding but inhibits nitric oxide-induced apoptosis in neuronal PC12 cells.

NGF is recognized for its role in neuronal differentiation and maintenance. Differentiation of PC12 cells by NGF involves p53, a transcription factor that controls growth arrest and apoptosis. We investigated NGF influence over p53 activity during NO-induced apoptosis by sodium nitroprusside in differentiated and mitotic PC12 cells. NGF-differentiation produced increased p53 levels, nuclear localization and sequence-specific DNA binding. Apoptosis in mitotic cells also produced these events but the accompanying activation of caspases 1-10 and mitochondrial depolarization were inhibited during NGF differentiation and could be reversed in p53-silenced cells. Transcriptional regulation of PUMA and survivin expression were not inhibited by NGF, although NO-induced mitochondrial depolarization was dependent upon de novo gene transcription and only occurred in mitotic cells. We conclude that NGF mediates prosurvival signaling by increasing factors such as Bcl-2 and p21(Waf1/Cip1) without altering p53 transcriptional activity to inhibit mitochondrial depolarization, caspase activation and apoptosis.

The search for truth and freedom: ethical issues surrounding human cloning and stem cell research.

The reality of cloning and stem cell research has provoked wonder, fear and anger. These developments have the potential fundamentally to alter humanity. But how well informed is the range of views being expressed? Is progress being threatened by understandable but uninformed fears? Or are scientists rushing toward an ethical abyss, so concerned with what they can do that they never stop to ask what they should do? This article identifies some of the fears and hopes surrounding cloning and stem cell research. It aims to provoke ethical debate in evaluating such research.