Extending the applicability of the dose addition model to the assessment of chemical mixtures of partial agonists by using a novel toxic unit extrapolation method

This article has been made available through the Brunel Open Access Publishing Fund.Dose addition, a commonly used concept in toxicology for the prediction of chemical mixture effects, cannot readily be applied to mixtures of partial agonists with differing maximal effects. Due to its mathematical features, effect levels that exceed the maximal effect of the least efficacious compound present in the mixture, cannot be calculated. This poses problems when dealing with mixtures likely to be encountered in realistic assessment situations where chemicals often show differing maximal effects. To overcome this limitation, we developed a pragmatic solution that extrapolates the toxic units of partial agonists to effect levels beyond their maximal efficacy. We extrapolated different additivity expectations that reflect theoretically possible extremes and validated this approach with a mixture of 21 estrogenic chemicals in the E-Screen. This assay measures the proliferation of human epithelial breast cancers. We found that the dose-response curves of the estrogenic agents exhibited widely varying shapes, slopes and maximal effects, which made it necessary to extrapolate mixture responses above 14% proliferation. Our toxic unit extrapolation approach predicted all mixture responses accurately. It extends the applicability of dose addition to combinations of agents with differing saturating effects and removes an important bottleneck that has severely hampered the use of dose addition in the past. © 2014 Scholze et al

A bi‐organellar phylogenomic study of Pandanales: inference of higher‐order relationships and unusual rate‐variation patterns

We used a bi‐organellar phylogenomic approach to address higher‐order relationships in Pandanales, including the first molecular phylogenetic study of the panama‐hat family, Cyclanthaceae. Our genus‐level study of plastid and mitochondrial gene sets includes a comprehensive sampling of photosynthetic lineages across the order, and provides a framework for investigating clade ages, biogeographic hypotheses and organellar molecular evolution. Using multiple inference methods and both organellar genomes, we recovered mostly congruent and strongly supported relationships within and between families, including the placement of fully mycoheterotrophic Triuridaceae. Cyclanthaceae and Pandanaceae plastomes have slow substitution rates, contributing to weakly supported plastid‐based relationships in Cyclanthaceae. While generally slowly evolving, mitochondrial genomes exhibit sporadic rate elevation across the order. However, we infer well‐supported relationships even for slower evolving mitochondrial lineages in Cyclanthaceae. Clade age estimates across photosynthetic lineages are largely consistent with previous studies, are well correlated between the two organellar genomes (with slightly younger inferences from mitochondrial data), and support several biogeographic hypotheses. We show that rapidly evolving non‐photosynthetic lineages may bias age estimates upwards at neighbouring photosynthetic nodes, even using a relaxed clock model. Finally, we uncovered new genome structural variants in photosynthetic taxa at plastid inverted repeat boundaries that show promise as interfamilial phylogenetic markers.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162810/33/cla12417-sup-0025-TableS1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162810/32/cla12417-sup-0017-FigS17.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162810/31/cla12417-sup-0004-FigS4.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162810/30/cla12417-sup-0019-FigS19.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162810/29/cla12417-sup-0020-FigS20.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162810/28/cla12417_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162810/27/cla12417-sup-0005-FigS5.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162810/26/cla12417-sup-0012-FigS12.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162810/25/cla12417-sup-0007-FigS7.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162810/24/cla12417-sup-0022-FigS22.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162810/23/cla12417-sup-0029-TableS5.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162810/22/cla12417-sup-0010-FigS10.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162810/21/cla12417-sup-0011-FigS11.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162810/20/cla12417-sup-0014-FigS14.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162810/19/cla12417-sup-0002-FigS2.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162810/18/cla12417-sup-0001-FigS1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162810/17/cla12417.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162810/16/cla12417-sup-0030-TableS6.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162810/15/cla12417-sup-0021-FigS21.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162810/14/cla12417-sup-0023-FigS23.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162810/13/cla12417-sup-0009-FigS9.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162810/12/cla12417-sup-0031-TableS7.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162810/11/cla12417-sup-0006-FigS6.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162810/10/cla12417-sup-0003-FigS3.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162810/9/cla12417-sup-0024-FigS24.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162810/8/cla12417-sup-0008-FigS8.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162810/7/cla12417-sup-0028-TableS4.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162810/6/cla12417-sup-0016-FigS16.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162810/5/cla12417-sup-0013-FigS13.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162810/4/cla12417-sup-0018-FigS18.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162810/3/cla12417-sup-0026-TableS2.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162810/2/cla12417-sup-0015-FigS15.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162810/1/cla12417-sup-0027-TableS3.pd

A molecular line scan in the Hubble Deep Field North

We present a molecular line scan in the Hubble Deep Field North (HDF-N) that covers the entire 3mm window (79-115 GHz) using the IRAM Plateau de Bure Interferometer. Our CO redshift coverage spans z2. We reach a CO detection limit that is deep enough to detect essentially all z>1 CO lines reported in the literature so far. We have developed and applied different line searching algorithms, resulting in the discovery of 17 line candidates. We estimate that the rate of false positive line detections is ~2/17. We identify optical/NIR counterparts from the deep ancillary database of the HDF-N for seven of these candidates and investigate their available SEDs. Two secure CO detections in our scan are identified with star-forming galaxies at z=1.784 and at z=2.047. These galaxies have colors consistent with the `BzK' color selection and they show relatively bright CO emission compared with galaxies of similar dust continuum luminosity. We also detect two spectral lines in the submillimeter galaxy HDF850.1 at z=5.183. We consider an additional 9 line candidates as high quality. Our observations also provide a deep 3mm continuum map (1-sigma noise level = 8.6 μJy/beam). Via a stacking approach, we find that optical/MIR bright galaxies contribute only to <50% of the SFR density at 1<z<3, unless high dust temperatures are invoked. The present study represents a first, fundamental step towards an unbiased census of molecular gas in `normal' galaxies at high-z, a crucial goal of extragalactic astronomy in the ALMA era

The Infrared Behaviour of the Pure Yang-Mills Green Functions

We review the infrared properties of the pure Yang-Mills correlators and discuss recent results concerning the two classes of low-momentum solutions for them reported in literature; i.e. decoupling and scaling solutions. We will mainly focuss on the Landau gauge and pay special attention to the results inferred from the analysis of the Dyson-Schwinger equations of the theory and from "{\it quenched}" lattice QCD. The results obtained from properly interplaying both approaches are strongly emphasized.Comment: Final version to be published in FBS (54 pgs., 11 figs., 4 tabs

A conceptual framework for crop-based agri-food supply chain characterization under uncertainty

[EN] Crop-based Agri-food Supply Chains (AFSCs) are complex systems that face multiple sources of uncertainty that can cause a significant imbalance between supply and demand in terms of product varieties, quantities, qualities, customer requirements, times and prices, all of which greatly complicate their management. Poor management of these sources of uncertainty in these AFSCs can have negative impact on quality, safety, and sustainability by reducing the logistic efficiency and increasing the waste. Therefore, it becomes crucial to develop models in order to deal with the key sources of uncertainty. For this purpose, it is necessary to precisely understand and define the problem under study. Even, the characterisation process of this domains is also a difficult and time-consuming task, especially when the right directions and standards are not in place. In this chapter, a Conceptual Framework is proposed that systematically collects those aspects that are relevant for an adequate crop-based AFSC management under uncertainty.Authors of this publication acknowledge the contribution of the Project 691249, RUC-APS "Enhancing and implementing Knowledge based ICT solutions within high Risk and Uncertain Conditions for Agriculture Production Systems" (www.ruc-aps.eu), funded by the European Union under their funding scheme H2020-MSCA-RISE-2015Alemany Díaz, MDM.; Esteso, A.; Ortiz Bas, Á.; Hernández Hormazabal, JE.; Fernández, A.; Garrido, A.; Martin, J.... (2021). A conceptual framework for crop-based agri-food supply chain characterization under uncertainty. Studies in Systems, Decision and Control. 280:19-33. https://doi.org/10.1007/978-3-030-51047-3_2S1933280Taylor, D.H., Fearne, A.: Towards a framework for improvement in the management of demand in agri-food supply chains. 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Formation and Growth of Oligomers: A Monte Carlo Study of an Amyloid Tau Fragment

Small oligomers formed early in the process of amyloid fibril formation may be the major toxic species in Alzheimer's disease. We investigate the early stages of amyloid aggregation for the tau fragment AcPHF6 (Ac-VQIVYK-NH2) using an implicit solvent all-atom model and extensive Monte Carlo simulations of 12, 24, and 36 chains. A variety of small metastable aggregates form and dissolve until an aggregate of a critical size and conformation arises. However, the stable oligomers, which are β-sheet-rich and feature many hydrophobic contacts, are not always growth-ready. The simulations indicate instead that these supercritical oligomers spend a lengthy period in equilibrium in which considerable reorganization takes place accompanied by exchange of chains with the solution. Growth competence of the stable oligomers correlates with the alignment of the strands in the β-sheets. The larger aggregates seen in our simulations are all composed of two twisted β-sheets, packed against each other with hydrophobic side chains at the sheet–sheet interface. These β-sandwiches show similarities with the proposed steric zipper structure for PHF6 fibrils but have a mixed parallel/antiparallel β-strand organization as opposed to the parallel organization found in experiments on fibrils. Interestingly, we find that the fraction of parallel β-sheet structure increases with aggregate size. We speculate that the reorganization of the β-sheets into parallel ones is an important rate-limiting step in the formation of PHF6 fibrils

A diarylamine derived from anthranilic acid inhibits ZIKV replication

Zika virus (ZIKV) is a mosquito-transmitted Flavivirus, originally identified in Uganda in 1947 and recently associated with a large outbreak in South America. Despite extensive efforts there are currently no approved antiviral compounds for treatment of ZIKV infection. Here we describe the antiviral activity of diarylamines derived from anthranilic acid (FAMs) against ZIKV. A synthetic FAM (E3) demonstrated anti-ZIKV potential by reducing viral replication up to 86%. We analyzed the possible mechanisms of action of FAM E3 by evaluating the intercalation of this compound into the viral dsRNA and its interaction with the RNA polymerase of bacteriophage SP6. However, FAM E3 did not act by these mechanisms. In silico results predicted that FAM E3 might bind to the ZIKV NS3 helicase suggesting that this protein could be one possible target of this compound. To test this, the thermal stability and the ATPase activity of the ZIKV NS3 helicase domain (NS3Hel) were investigated in vitro and we demonstrated that FAM E3 could indeed bind to and stabilize NS3Hel