Pediatric allergic contact dermatitis (ACD) has been increasingly recognized in the United States. Reported rates of positive patch tests in children referred for suspected ACD range between 27 and 95.6%. Many young children are becoming sensitized to contact allergens found in personal hygiene products. We reviewed five recent pediatric patch test studies to determine the top allergens associated with this source of ACD in children. The top ten allergens were neomycin, balsam of Peru, fragrance mix, lanolin, cocamidopropylbetaine, formaldehyde, corticosteroids, methylchlorisothiazolinone (MCI)/methylisothiazolinone (MI), propylene glycol, and benzalkonium chloride. We estimate that one third of children suffering from ACD could potentially benefit from a 'pre-emptive avoidance strategy' (P.E.A.S.) of the stated top 10 allergens.

Despite convergence of overall breast cancer incidence rates between European American (EA) and African American (AA) women, disparities in mortality persist. The factors contributing to differences in mortality rates across population groups remain controversial and range from population genetics to sociodemographic influences. This review explores the complex multi-factorial nature of tumor-intrinsic and -extrinsic factors that impact the biology and clinical outcomes of breast cancer patients. In addition to summarizing the current state of breast cancer disparities research, we also motivate the development of integrative multi-scale approaches involving interdisciplinary teams to tackle this complex clinical challenge.

Carotenoid cleavage oxygenases (CCO) are non-heme iron enzymes that catalyze oxidative cleavage of alkene bonds in carotenoid and stilbenoid substrates. Previously, we showed that the iron cofactor of CAO1, a resveratrol-cleaving member of this family, can be substituted with cobalt to yield a catalytically inert enzyme useful for trapping active site-bound stilbenoid substrates for structural characterization. Metal substitution may provide a general method for identifying the natural substrates for CCOs in addition to facilitating structural and biophysical characterization of CCO-carotenoid complexes under normal aerobic conditions. Here, we demonstrate the general applicability of cobalt substitution in a prototypical carotenoid cleaving CCO, apocarotenoid oxygenase (ACO) from Synechocystis. Among the non-native divalent metals investigated, cobalt was uniquely able to stably occupy the ACO metal binding site and inhibit catalysis. Analysis by X-ray crystallography and X-ray absorption spectroscopy demonstrate that the Co(II) forms of both ACO and CAO1 exhibit a close structural correspondence to the native Fe(II) enzyme forms. Hence, cobalt substitution is an effective strategy for generating catalytically inert but structurally intact forms of CCOs.Electronic supplementary materialThe online version of this article (10.1007/s00775-018-1586-0) contains supplementary material, which is available to authorized users.

Edited by F. Peter Guengerich Carotenoid cleavage dioxygenases (CCDs) use a nonheme Fe(II) cofactor to split alkene bonds of carotenoid and stilbenoid substrates. The iron centers of CCDs are typically five-coordinate in their resting states, with solvent occupying an exchangeable site. The involvement of this iron-bound solvent in CCD catalysis has not been experimentally addressed, but computational studies suggest two possible roles. 1) Solvent dissociation provides a coordination site for O 2 , or 2) solvent remains bound to iron but changes its equilibrium position to allow O 2 binding and potentially acts as a proton source. To test these predictions, we investigated isotope effects (H 2 O versus D 2 O) on two stilbenoidcleaving CCDs, Novosphingobium aromaticivorans oxygenase 2 (NOV2) and Neurospora crassa carotenoid oxygenase 1 (CAO1), using piceatannol as a substrate. NOV2 exhibited an inverse isotope effect (k H /k D ϳ 0.6) in an air-saturated buffer, suggesting that solvent dissociates from iron during the catalytic cycle. By contrast, CAO1 displayed a normal isotope effect (k H /k D ϳ 1.7), suggesting proton transfer in the rate-limiting step. X-ray absorption spectroscopy on NOV2 and CAO1 indicated that the protonation states of the iron ligands are unchanged within pH 6.5-8.5 and that the Fe(II)-aquo bond is minimally altered by substrate binding. We pinpointed the origin of the differential kinetic behaviors of NOV2 and CAO1 to a single amino acid difference near the solvent-binding site of iron, and X-ray crystallography revealed that the substitution alters binding of diffusible ligands to the iron center. We conclude that solvent-iron dissociation and proton transfer are both associated with the CCD catalytic mechanism. Carotenoid cleavage dioxygenases (CCDs) 2 constitute a family of nonheme iron enzymes that catalyze the cleavage of alk-This work was supported by National Institutes of Health Grants R01EY009339 (to P. D. K.) and R01EY020551 (to J. v. L.), Department of Veterans Affairs Grant IK2BX002683 (to P. D. K.), and Burroughs Wellcome Fund Award 1015187 (to P. D. K.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Department of Veterans Affairs. This article contains Figs. S1-S8 and Tables S1 and S2.

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