Chemical Reaction of Soybean Flavonoids with DNA: A Computational Study Using the Implicit Solvent Model

Genistein, daidzein, glycitein and quercetin are flavonoids present in soybean and other vegetables in high amounts. These flavonoids can be metabolically converted to more active forms, which may react with guanine in the DNA to form complexes and can lead to DNA depurination. We assumed two ultimate carcinogen forms of each of these flavonoids, diol epoxide form and diketone form. Density functional theory (DFT) and Hartree-Fock (HF) methods were used to study the reaction thermodynamics between active forms of flavonoids and DNA guanine. Solvent reaction field method of Tomasi and co-workers and the Langevin dipoles method of Florian and Warshel were used to calculate the hydration free energies. Activation free energy for each reaction was estimated using the linear free energy relation. Our calculations show that diol epoxide forms of flavonoids are more reactive than the corresponding diketone forms and are hence more likely flavonoid ultimate carcinogens. Genistein, daidzein and glycitein show comparable reactivity while quercetin is less reactive toward DNA

Climbing the crustal ladder: Magma storage-depth evolution during a volcanic flare-up

© The Author(s), 2018. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Science Advances 4 (2018): eaap7567, doi:10.1126/sciadv.aap7567.Very large eruptions (>50 km3) and supereruptions (>450 km3) reveal Earth’s capacity to produce and store enormous quantities (>1000 km3) of crystal-poor, eruptible magma in the shallow crust. We explore the interplay between crustal evolution and volcanism during a volcanic flare-up in the Taupo Volcanic Zone (TVZ, New Zealand) using a combination of quartz-feldspar-melt equilibration pressures and time scales of quartz crystallization. Over the course of the flare-up, crystallization depths became progressively shallower, showing the gradual conditioning of the crust. Yet, quartz crystallization times were invariably very short (<100 years), demonstrating that very large reservoirs of eruptible magma were transient crustal features. We conclude that the dynamic nature of the TVZ crust favored magma eruption over storage. Episodic tapping of eruptible magmas likely prevented a supereruption. Instead, multiple very large bodies of eruptible magma were assembled and erupted in decadal time scales.This work was supported by the NSF (EAR-1151337) and by two Vanderbilt University Discovery Grants

Novel Regulation of CCL2 Gene Expression by Murine LITAF and STAT6B

Inflammation is a multifaceted process: beneficial as a defense mechanism but also detrimental depending on its severity and duration. At the site of injury, inflammatory cells are activated by a cascade of mediators, one of which is LITAF, a transcription regulator known to upregulate TNF-α. We previously showed that human LITAF forms a complex with human STAT6B, which translocates into the nucleus to upregulate cytokine transcription. To dissect the molecular implications of this complex, a murine model was developed and interactions between mouse STAT6B (mSTAT6B) and mouse LITAF (mLITAF) were analyzed. Both mLITAF and mSTAT6B expression were MyD88- and TLR ligand-dependent. Furthermore, mLITAF was found to mediate LPS-induced CCL2 gene transcription with the cooperation of mSTAT6B leading to CCL2 protein expression. In LITAF-deficient mice, mLITAF-mediated CCL2 production in macrophages was significantly reduced compared to the wild-type control animals. Mice knockdown for mSTAT6B by 6BsiRNA1 tail vein injection resulted in a decrease in serum TNF-α and CCL2 production. mLITAF/mSTAT6B complex is proposed to play a role in LPS-induced CCL2 expression and possibly other cytokines

Timescales of Quartz Crystallization and the Longevity of the Bishop Giant Magma Body

Supereruptions violently transfer huge amounts (100 s–1000 s km3) of magma to the surface in a matter of days and testify to the existence of giant pools of magma at depth. The longevity of these giant magma bodies is of significant scientific and societal interest. Radiometric data on whole rocks, glasses, feldspar and zircon crystals have been used to suggest that the Bishop Tuff giant magma body, which erupted ∼760,000 years ago and created the Long Valley caldera (California), was long-lived (>100,000 years) and evolved rather slowly. In this work, we present four lines of evidence to constrain the timescales of crystallization of the Bishop magma body: (1) quartz residence times based on diffusional relaxation of Ti profiles, (2) quartz residence times based on the kinetics of faceting of melt inclusions, (3) quartz and feldspar crystallization times derived using quartz+feldspar crystal size distributions, and (4) timescales of cooling and crystallization based on thermodynamic and heat flow modeling. All of our estimates suggest quartz crystallization on timescales of <10,000 years, more typically within 500–3,000 years before eruption. We conclude that large-volume, crystal-poor magma bodies are ephemeral features that, once established, evolve on millennial timescales. We also suggest that zircon crystals, rather than recording the timescales of crystallization of a large pool of crystal-poor magma, record the extended periods of time necessary for maturation of the crust and establishment of these giant magma bodies

Environmental Electrokinetics for a sustainable subsurface

International audienceSoil and groundwater are key components in the sustainable management of the subsurface environment. Source contamination is one of its main threats and is commonly addressed using established remediation techniques such as in-situ chemical oxidation (ISCO), in-situ chemical reduction (ISCR; most notably using zero-valent iron [ZVI]), enhanced in-situ bioremediation (EISB), phytoremediation, soil-washing, pump-and-treat, soil vapour extraction (SVE), thermal treatment, and excavation and disposal. Decades of field applications have shown that these techniques can successfully treat or control contaminants in higher permeability subsurface materials such as sands, but achieve only limited success at sites where low permeability soils, such as silts and clays, prevail. Electrokinetics (EK), a soil remediation technique mostly recognized in in-situ treatment of low permeability soils, has, for the last decade, been combined with more conventional techniques and can significantly enhance the performance of several of these remediation technologies, including ISCO, ISCR, EISB and phytoremediation. Herein, we discuss the use of emerging EK techniques in tandem with conventional remediation techniques, to achieve improved remediation performance. Furthermore, we highlight new EK applications that may come to play a role in the sustainable treatment of the contaminated subsurface

Azithromycin reduces spontaneous and induced inflammation in ΔF508 cystic fibrosis mice

BACKGROUND: Inflammation plays a critical role in lung disease development and progression in cystic fibrosis. Azithromycin is used for the treatment of cystic fibrosis lung disease, although its mechanisms of action are poorly understood. We tested the hypothesis that azithromycin modulates lung inflammation in cystic fibrosis mice. METHODS: We monitored cellular and molecular inflammatory markers in lungs of cystic fibrosis mutant mice homozygous for the ΔF508 mutation and their littermate controls, either in baseline conditions or after induction of acute inflammation by intratracheal instillation of lipopolysaccharide from Pseudomonas aeruginosa, which would be independent of interactions of bacteria with epithelial cells. The effect of azithromycin pretreatment (10 mg/kg/day) given by oral administration for 4 weeks was evaluated. RESULTS: In naive cystic fibrosis mice, a spontaneous lung inflammation was observed, characterized by macrophage and neutrophil infiltration, and increased intra-luminal content of the pro-inflammatory cytokine macrophage inflammatory protein-2. After induced inflammation, cystic fibrosis mice combined exaggerated cellular infiltration and lower anti-inflammatory interleukin-10 production. In cystic fibrosis mice, azithromycin attenuated cellular infiltration in both baseline and induced inflammatory condition, and inhibited cytokine (tumor necrosis factor-α and macrophage inflammatory protein-2) release in lipopolysaccharide-induced inflammation. CONCLUSION: Our findings further support the concept that inflammatory responses are upregulated in cystic fibrosis. Azithromycin reduces some lung inflammation outcome measures in cystic fibrosis mice. We postulate that some of the benefits of azithromycin treatment in cystic fibrosis patients are due to modulation of lung inflammation

Human Genetics in Rheumatoid Arthritis Guides a High-Throughput Drug Screen of the CD40 Signaling Pathway

Although genetic and non-genetic studies in mouse and human implicate the CD40 pathway in rheumatoid arthritis (RA), there are no approved drugs that inhibit CD40 signaling for clinical care in RA or any other disease. Here, we sought to understand the biological consequences of a CD40 risk variant in RA discovered by a previous genome-wide association study (GWAS) and to perform a high-throughput drug screen for modulators of CD40 signaling based on human genetic findings. First, we fine-map the CD40 risk locus in 7,222 seropositive RA patients and 15,870 controls, together with deep sequencing of CD40 coding exons in 500 RA cases and 650 controls, to identify a single SNP that explains the entire signal of association (rs4810485, P = 1.4×10(−9)). Second, we demonstrate that subjects homozygous for the RA risk allele have ∼33% more CD40 on the surface of primary human CD19+ B lymphocytes than subjects homozygous for the non-risk allele (P = 10(−9)), a finding corroborated by expression quantitative trait loci (eQTL) analysis in peripheral blood mononuclear cells from 1,469 healthy control individuals. Third, we use retroviral shRNA infection to perturb the amount of CD40 on the surface of a human B lymphocyte cell line (BL2) and observe a direct correlation between amount of CD40 protein and phosphorylation of RelA (p65), a subunit of the NF-κB transcription factor. Finally, we develop a high-throughput NF-κB luciferase reporter assay in BL2 cells activated with trimerized CD40 ligand (tCD40L) and conduct an HTS of 1,982 chemical compounds and FDA–approved drugs. After a series of counter-screens and testing in primary human CD19+ B cells, we identify 2 novel chemical inhibitors not previously implicated in inflammation or CD40-mediated NF-κB signaling. Our study demonstrates proof-of-concept that human genetics can be used to guide the development of phenotype-based, high-throughput small-molecule screens to identify potential novel therapies in complex traits such as RA

Toxicological aspects of the use of phenolic compounds in disease prevention

The consumption of a diet low in fat and enhanced by fruits and vegetables, especially rich in phenolic compounds, may reduce risks of many civilization diseases. The use of traditional medicines, mainly derived from plant sources, has become an attractive segment in the management of many lifestyle diseases. Concerning the application of dietary supplements (based on phenolic compounds) in common practice, the ongoing debate over possible adverse effects of certain nutrients and dosage levels is of great importance. Since dietary supplements are not classified as drugs, their potential toxicities and interactions have not been thoroughly evaluated. First, this review will introduce phenolic compounds as natural substances beneficial for human health. Second, the potential dual mode of action of flavonoids will be outlined. Third, potential deleterious impacts of phenolic compounds utilization will be discussed: pro-oxidant and estrogenic activities, cancerogenic potential, cytotoxic effects, apoptosis induction and flavonoid-drug interaction. Finally, future trends within the research field will be indicated