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Deoxynivalenol (DON) is a mycotoxin primarily produced by Fusarium fungi, occurring predominantly in cereal grains. Following the request of the European Commission, the CONTAM Panel assessed the risk to animal and human health related to DON, 3-acetyl-DON (3-Ac-DON), 15-acetyl-DON (15-Ac-DON) and DON-3-glucoside in food and feed. A total of 27,537, 13,892, 7,270 and 2,266 analytical data for DON, 3-Ac-DON, 15-Ac-DON and DON-3-glucoside, respectively, in food, feed and unprocessed grains collected from 2007 to 2014 were used. For human exposure, grains and grain-based products were main sources, whereas in farm and companion animals, cereal grains, cereal by-products and forage maize contributed most. DON is rapidly absorbed, distributed, and excreted. Since 3-Ac-DON and 15-Ac-DON are largely deacetylated and DON-3-glucoside cleaved in the intestines the same toxic effects as DON can be expected. The TDI of 1 lg/kg bw per day, that was established for DON based on reduced body weight gain in mice, was therefore used as a group-TDI for the sum of DON, 3-Ac-DON, 15-Ac-DON and DON-3-glucoside. In order to assess acute human health risk, epidemiological data from mycotoxicoses were assessed and a group-ARfD of 8 lg/kg bw per eating occasion was calculated. Estimates of acute dietary exposures were below this dose and did not raise a health concern in humans. The estimated mean chronic dietary exposure was above the group-TDI in infants, toddlers and other children, and at high exposure also in adolescents and adults, indicating a potential health concern. Based on estimated mean dietary concentrations in ruminants, poultry, rabbits, dogs and cats, most farmed fish species and horses, adverse effects are not expected. At the high dietary concentrations, there is a potential risk for chronic adverse effects in pigs and fish and for acute adverse effects in cats and farmed mink.This is an open access article under the terms of the Creative Commons Attribution-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited and no modifications or adaptations are made.The EFSA Journal is a publication of the European Food Safety Authority, an agency of the European Union. Deoxynivalenol and its acetylated and modified forms in food and feed www.efsa.europa.eu/efsajournal 2 EFSA Journal 2017;15(9):4718 Deoxynivalenol and its acetylated and modified forms in food and feed www.efsa.europa.eu/efsajournal 3 EFSA Journal 2017;15(9):4718 Deoxynivalenol and its acetylated and modified forms in food and feed www.efsa.europa.eu/efsajournal 4 EFSA Journal 2017;15(9):471870% of ingested DON is excreted via urine, of which about 80% was in conjugated forms, mainly as DON-15-glucuronide that was about threefold more efficiently formed than DON-3-glucuronide. After a single oral exposure to DON, feed refusal appeared very quickly in mice. Previous risk assessments of DON conducted by the Scientific Committee on Food (SCF) in 1999 and by the Joint FAO/WHO Expert Committee on Food Additives...

Earlier we reported the discovery and design of NBD-556 and their analogs which demonstrated their potential as HIV-1 entry inhibitors. However, progress in developing these inhibitors has been stymied by their CD4-agonist properties, an unfavorable trait for use as drug. Here, we demonstrate the successful conversion of a full CD4-agonist (NBD-556) through a partial CD4-agonist (NBD-09027), to a full CD4-antagonist (NBD-11021) by structure-based modification of the critical oxalamide midregion, previously thought to be intolerant of modification. NBD-11021 showed unprecedented neutralization breath for this class of inhibitors, with pan-neutralization against a panel of 56 Env-pseudotyped HIV-1 representing diverse subtypes of clinical isolates (IC50 as low as 270 nM). The cocrystal structure of NBD-11021 complexed to a monomeric HIV-1 gp120 core revealed its detail binding characteristics. The study is expected to provide a framework for further development of NBD series as HIV-1 entry inhibitors for clinical application against AIDS.

Establishing methods for controlling aspects of large amplitude submolecular movements is a prerequisite for the development of artificial devices that function through rotary motion at the molecular level. Here we demonstrate that the rate of rotation of the interlocked components of fumaramide-derived [2]rotaxanes can be accelerated, by >6 orders of magnitude, by isomerizing them to the corresponding maleamide [2]rotaxanes by using light. molecular machines ͉ dynamics L arge amplitude internal rotations that resemble to some extent processes found in authentic machinery have recently inspired analogic molecular versions of gears (1), turnstiles (2), brakes (3), ratchets (4, 5), rotors (6), and unidirectional spinning motors (7-10) and are an inherent characteristic of many catenanes and rotaxanes (11-13). Establishing methods for controlling aspects of such movements is a prerequisite for the development of artificial devices that function through rotary motion at the molecular level. In this regard, we recently reported the unexpected discovery that the rate of rotation of the interlocked components of benzylic amide macrocyclecontaining nitrone and fumaramide [2]rotaxanes can be slowed (''dampened'') by 2-3 orders of magnitude by applying a modest (Ϸ1 V⅐cm Ϫ1) external oscillating electric field (14). Here we demonstrate that the rate of rotation of the interlocked components of the olefin-based rotaxanes can also be accelerated, by Ͼ6 orders of magnitude, using another broadly useful stimulus, light.Fumaramide threads template the assembly of benzylic amide macrocycles around them to form rotaxanes in high yields (15). This cheap and simple preparative procedure (suitable threads are prepared in a single step from fumaryl chloride and a bulky primary or secondary amine) is particularly efficient because the trans-olefin fixes the two hydrogen bond-accepting groups of the thread in an arrangement that is complementary to the geometry of the hydrogen bonddonating sites of the forming macrocycle. However, the feature of the fumaramide unit that makes it such an effective template also provides an opportunity to enforce a geometrical change in the thread after rotaxane formation, thus altering the nature and strength of the interactions between the interlocked components. Isomerization of the olefin from E-to Z-must necessarily disrupt the near-ideal hydrogen bonding motif between macrocycle and thread and therefore also change any internal dynamics governed by those interactions.To test this idea, the photochemical isomerization of three fumaramide-based threads (E-1-3) and rotaxanes (E-4-6) was investigated. The synthesis of rotaxanes E-4 and E-6 has been described (15), and E-5 was prepared in analogous fashion from the corresponding thread, E-2, isophthaloyl dichloride and p-xylylene diamine (Scheme 1).** Under the same reaction conditions the cis-olefin (maleamide) threads, Z-1-3, did not give detectable quantities of the corresponding Z-rotaxanes. Experimental ProceduresGeneral Method for the Photoisomeri...

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In our attempt to optimize the lead HIV-1 entry antagonist, NBD-11021, we present in this study the rational design and synthesis of 60 new analogues and determination of their antiviral activity in a single-cycle and a multicycle infection assay to derive a comprehensive structure-activity relationship (SAR). Two of these compounds, NBD-14088 and NBD-14107, showed significant improvement in antiviral activity compared to the lead entry antagonist in a single-cycle assay against a large panel of Env-pseudotyped viruses. The X-ray structure of a similar compound, NBD-14010, confirmed the binding mode of the newly designed compounds. The in vitro ADMET profiles of these compounds are comparable to that of the most potent attachment inhibitor BMS-626529, a prodrug of which is currently undergoing phase III clinical trials. The systematic study presented here is expected to pave the way for improving the potency, toxicity, and ADMET profile of this series of compounds with the potential to be moved to the early preclinical development.