Lineage-dependent effects of aryl hydrocarbon receptor agonists contribute to liver tumorigenesis

Rodent cancer bioassays indicate that the aryl hydrocarbon receptor (AHR) agonist, 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD), causes increases in both hepatocytic and cholangiocytic tumors. Effects of AHR activation have been evaluated on rodent hepatic stem cells (rHpSCs) versus their descendants, hepatoblasts (rHBs), two lineage stages of multipotent, hepatic precursors with overlapping but also distinct phenotypic traits. This was made possible by defining the first successful culture conditions for ex vivo maintenance of rHpScs consisting of a substratum of hyaluronans and Kubota's medium (KM), a serum-free medium designed for endodermal stem/progenitor cells. Supplementation of KM with leukemia inhibitory factor elicited lineage restriction to rHBs. Cultures were treated with various AHR agonists including TCDD, 6-formylindolo-[3,2-b]carbazole (FICZ), and 3-3'-diindolylmethane (DIM) and then analyzed with a combination of immunocytochemistry, gene expression, and high-content image analysis. The AHR agonists increased proliferation of rHpSCs at concentrations producing a persistent AHR activation as indicated by induction of Cyp1a1. By contrast, treatment with TCDD resulted in a rapid loss of viability of rHBs, even though the culture conditions, in the absence of the agonists, were permissive for survival and expansion of rHBs. The effects were not observed with FICZ and at lower concentrations of DIM. Conclusion: Our findings are consistent with a lineage-dependent mode of action for AHR agonists in rodent liver tumorigenesis through selective expansion of rHpSCs in combination with a toxicity-induced loss of viability of rHBs. These lineage-dependent effects correlate with increased frequency of liver tumors. (Hepatology 2015;61:548-560

An epigenetic clock for human skeletal muscle.

BACKGROUND: Ageing is associated with DNA methylation changes in all human tissues, and epigenetic markers can estimate chronological age based on DNA methylation patterns across tissues. However, the construction of the original pan-tissue epigenetic clock did not include skeletal muscle samples and hence exhibited a strong deviation between DNA methylation and chronological age in this tissue. METHODS: To address this, we developed a more accurate, muscle-specific epigenetic clock based on the genome-wide DNA methylation data of 682 skeletal muscle samples from 12 independent datasets (18-89 years old, 22% women, 99% Caucasian), all generated with Illumina HumanMethylation (HM) arrays (HM27, HM450, or HMEPIC). We also took advantage of the large number of samples to conduct an epigenome-wide association study of age-associated DNA methylation patterns in skeletal muscle. RESULTS: The newly developed clock uses 200 cytosine-phosphate-guanine dinucleotides to estimate chronological age in skeletal muscle, 16 of which are in common with the 353 cytosine-phosphate-guanine dinucleotides of the pan-tissue clock. The muscle clock outperformed the pan-tissue clock, with a median error of only 4.6 years across datasets (vs. 13.1 years for the pan-tissue clock, P < 0.0001) and an average correlation of ρ = 0.62 between actual and predicted age across datasets (vs. ρ = 0.51 for the pan-tissue clock). Lastly, we identified 180 differentially methylated regions with age in skeletal muscle at a false discovery rate < 0.005. However, gene set enrichment analysis did not reveal any enrichment for gene ontologies. CONCLUSIONS: We have developed a muscle-specific epigenetic clock that predicts age with better accuracy than the pan-tissue clock. We implemented the muscle clock in an r package called Muscle Epigenetic Age Test available on Bioconductor to estimate epigenetic age in skeletal muscle samples. This clock may prove valuable in assessing the impact of environmental factors, such as exercise and diet, on muscle-specific biological ageing processes

High-Pressure Transformation of SiO2 Glass from a Tetrahedral to an Octahedral Network:A Joint Approach Using Neutron Diffraction and Molecular Dynamics

International audienceA combination of in situ high-pressure neutron diffraction at pressures up to 17.5(5) GPa and moleculardynamics simulations employing a many-body interatomic potential model is used to investigate thestructure of cold-compressed silica glass. The simulations give a good account of the neutron diffractionresults and of existing x-ray diffraction results at pressures up to ∼60 GPa. On the basis of the moleculardynamics results, an atomistic model for densification is proposed in which rings are “zipped” by a pairingof five- and/or sixfold coordinated Si sites. The model gives an accurate description for the dependence ofthe mean primitive ring size hni on the mean Si-O coordination number, thereby linking a parameter that issensitive to ordering on multiple length scales to a readily measurable parameter that describes the localcoordination environment

Usage Bibliometrics

Scholarly usage data provides unique opportunities to address the known shortcomings of citation analysis. However, the collection, processing and analysis of usage data remains an area of active research. This article provides a review of the state-of-the-art in usage-based informetric, i.e. the use of usage data to study the scholarly process.Comment: Publisher's PDF (by permission). Publisher web site: books.infotoday.com/asist/arist44.shtm

Carbohydrate Dose Influences Liver and Muscle Glycogen Oxidation and Performance during Prolonged Exercise

This study investigated the effect of carbohydrate (CHO) dose and composi-tion on fuel selection during exercise, specifically exogenous and endogenous(liver and muscle) CHO oxidation. Ten trained males cycled in a double-blindrandomized order on 5 occasions at 77%_VO2maxfor 2 h, followed by a30-min time-trial (TT) while ingesting either 60 g�h�1(LG) or 75 g�h�113C-glucose (HG), 90 g�h�1(LGF) or 112.5 g�h�113C-glucose-13C-fructose ([2:1]HGF) or placebo. CHO doses met or exceed reported intestinal transportersaturation for glucose and fructose. Indirect calorimetry and stable mass iso-tope [13C] tracer techniques were utilized to determine fuel use. TT perfor-mance was 93% “likely/probable” to be improved with LGF compared withthe other CHO doses. Exogenous CHO oxidation was higher for LGF andHGF compared with LG and HG (ES&gt;1.34,P&lt;0.01), with the relative con-tribution of LGF (24.5�5.3%)moderatelyhigher than HGF (20.6�6.2%,ES=0.68). Increasing CHO dose beyond intestinal saturation increased abso-lute (29.2�28.6 g�h�1,ES=1.28,P=0.06) and relative muscle glycogenutilization (9.2�6.9%, ES=1.68,P=0.014) for glucose-fructose ingestion.Absolute muscle glycogen oxidation between LG and HG was not significantlydifferent, but wasmoderatelyhigher for HG (ES=0.60). Liver glycogen oxida-tion was not significantly different between conditions, but absolute and rela-tive contributions weremoderatelyattenuated for LGF (19.3�9.4 g�h�1,6.8�3.1%) compared with HGF (30.5�17.7 g�h�1, 10.1�4.0%, ES=0.79& 0.98). Total fat oxidation was suppressed in HGF compared with all otherCHO conditions (ES&gt;0.90,P=0.024–0.17). In conclusion, there was no lin-ear dose response for CHO ingestion, with 90 g�h�1of glucose-fructose beingoptimal in terms of TT performance and fuel selectio

Changes in body composition and performance with supplemental HMB-FA+ATP (Manuscript Clarification)

Additional co-authors: Matthew D. Vukovich, Colin Wilborn, and Darryn S. Willoughb

Incorporating New Technologies Into Toxicity Testing and Risk Assessment: Moving From 21st Century Vision to a Data-Driven Framework

Based on existing data and previous work, a series of studies is proposed as a basis toward a pragmatic early step in transforming toxicity testing. These studies were assembled into a data-driven framework that invokes successive tiers of testing with margin of exposure (MOE) as the primary metric. The first tier of the framework integrates data from high-throughput in vitro assays, in vitro-to-in vivo extrapolation (IVIVE) pharmacokinetic modeling, and exposure modeling. The in vitro assays are used to separate chemicals based on their relative selectivity in interacting with biological targets and identify the concentration at which these interactions occur. The IVIVE modeling converts in vitro concentrations into external dose for calculation of the point of departure (POD) and comparisons to human exposure estimates to yield a MOE. The second tier involves short-term in vivo studies, expanded pharmacokinetic evaluations, and refined human exposure estimates. The results from the second tier studies provide more accurate estimates of the POD and the MOE. The third tier contains the traditional animal studies currently used to assess chemical safety. In each tier, the POD for selective chemicals is based primarily on endpoints associated with a proposed mode of action, whereas the POD for nonselective chemicals is based on potential biological perturbation. Based on the MOE, a significant percentage of chemicals evaluated in the first 2 tiers could be eliminated from further testing. The framework provides a risk-based and animal-sparing approach to evaluate chemical safety, drawing broadly from previous experience but incorporating technological advances to increase efficiency

Disturbance and Plant Succession in the Mojave and Sonoran Deserts of the American Southwest

Disturbances such as fire, land clearing, and road building remove vegetation and can have major influences on public health through effects on air quality, aesthetics, recreational opportunities, natural resource availability, and economics. Plant recovery and succession following disturbance are poorly understood in arid lands relative to more temperate regions. This study quantitatively reviewed vegetation reestablishment following a variety of disturbances in the Mojave and Sonoran Deserts of southwestern North America. A total of 47 studies met inclusion criteria for the review. The time estimated by 29 individual studies for full reestablishment of total perennial plant cover was 76 years. Although long, this time was shorter than an estimated 215 years (among 31 individual studies) required for the recovery of species composition typical of undisturbed areas, assuming that recovery remains linear following the longest time since disturbance measurement made by the studies

The short-term effect of high versus moderate protein intake on recovery after strength training in resistance-trained individuals

Background: Dietary protein intakes up to 2.9 g.kg-1.d-1 and protein consumption before and after resistance training may enhance recovery, resulting in hypertrophy and strength gains. However, it remains unclear whether protein quantity or nutrient timing is central to positive adaptations. This study investigated the effect of total dietary protein content, whilst controlling for protein timing, on recovery in resistance trainees. Methods: Fourteen resistance-trained individuals underwent two 10-day isocaloric dietary regimes with a protein content of 1.8 g.kg-1.d-1 (PROMOD) or 2.9 g.kg-1.d-1 (PROHIGH) in a randomised, counterbalanced, crossover design. On days 8-10 (T1-T3), participants undertook resistance exercise under controlled conditions, performing 3 sets of squat, bench press and bent-over rows at 80% 1 repetition maximum until volitional exhaustion. Additionally, participants consumed a 0.4 g.kg-1 whey protein concentrate/isolate mix 30 minutes before and after exercise sessions to standardise protein timing specific to training. Recovery was assessed via daily repetition performance, muscle soreness, bioelectrical impedance phase angle, plasma creatine kinase (CK) and tumor necrosis factor-α (TNF-α). Results: No significant differences were reported between conditions for any of the performance repetition count variables (p>0.05). However, within PROMOD only, squat performance total repetition count was significantly lower at T3 (19.7 ± 6.8) compared to T1 (23.0 ± 7.5; p=0.006). Pre and post-exercise CK concentrations significantly increased across test days (p≤0.003), although no differences were reported between conditions. No differences for TNF-α or muscle soreness were reported between dietary conditions. Phase angle was significantly greater at T3 for PROHIGH (8.26 ± 0.82°) compared with PROMOD (8.08 ± 0.80°; p=0.012). Conclusions: When energy intake and peri-exercise protein intake was controlled for, a short term PROHIGH diet did not improve markers of muscle damage or soreness in comparison to a PROMOD approach following repeated days of intensive training. Whilst it is therefore likely that protein intakes (1.8g.kg-1.d-1) may be sufficient for resistance-trained individuals, it is noteworthy that both lower body exercise performance and bioelectrical phase angle were maintained with PROHIGH. Longer term interventions are warranted to determine whether PROMOD intakes are sufficient during prolonged training periods or when extensive exercise (e.g. training twice daily) is undertaken

Evolution and dynamics of a fold-thrust belt: The Sulaiman Range of Pakistan

We present observations and models of the Sulaiman Range of western Pakistan that shed new light on the evolution and deformation of fold-thrust belts. Earthquake source inversions show that the seismic deformation in the range is concentrated in the thick pile of sediments overlying the underthrusting lithosphere of the Indian subcontinent. The slip vectors of the earthquakes vary in strike around the margin of the range, in tandem with the shape of the topography, suggesting that gravitational driving forces arising from the topography play an important role in governing the deformation of the region. Numerical models suggest that the active deformation, and the extreme plan-view curvature of the range, are governed by the presence of weak sediments in a pre-existing basin on the underthrusting Indian Plate. These sediments affect the stress-state in the over-riding mountain range and allow for the rapid propagation of the nose of the range and the development of extreme curvature and laterally varying surface gradients.This study forms part of the NERC- and ESRC-funded project ‘Earthquakes Without Frontiers’. Our thanks go to Jerome Neufeld for many interesting coffee-time discussions, and James Jackson and Dan McKenzie, for comments on the manuscript. We thank Chris Morley and one anonymous reviewer for helpful comments on the manuscript.This article has been accepted for publication in in Geophysical Journal International ©: (2015) 201(2): 683-710, doi: 10.1093/gji/ggv005 , First published online March 9, 2015, Published by Oxford University Press on behalf of the Royal Astronomical Society. All rights reserved