System confluence and the reinvention of automobility.

The aim of the paper is to provide a longitudinal account of the emergence and stabilization of the automobility system and to assess the contemporary state of the system in the early stages of an ongoing sustainability transition. The production, use, and disposal of cars, in a pervasive global automobility system, are examined to reveal and explain the growing sustainability significance of overlaps with other systems. System-to-system confluence to varying degrees is ongoing with electricity, housing, aerospace, and information, software, and communications systems. The interfaces between multiple systems are evidenced by contestation for legitimacy via technological innovation and organizational experimentation. The result is uncertainty among key actors and stakeholders, institutional reforms, diverse corporate strategies, and emergent societal practices and behaviors. The paper thereby provides a contextualized account of the tension between barriers to change that may preserve the coherence of the automobility system and differential boundary effects arising from the impact of other production-consumption systems that may result in regime fragmentation. Confluence with other systems may resolve some sustainability contradictions but will also create new ones. Appeal to sustainability science will be key to evaluating how far existing sustainability problems will be resolved, and how far new ones will emerge in the automobility transition.

Introducing a Dynamic Reconstruction Methodology for Multilayered Structures in Atom Probe Tomography.

Atom probe tomography (APT) is a powerful three-dimensional nanoanalyzing microscopy technique considered key in modern materials science. However, progress in the spatial reconstruction of APT data has been rather limited since the first implementation of the protocol proposed by Bas et al. in 1995. This paper proposes a simple semianalytical approach to reconstruct multilayered structures, i.e., two or more different compounds stacked perpendicular to the analysis direction. Using a field evaporation model, the general dynamic evolution of parameters involved in the reconstruction of this type of structure is estimated. Some experimental reconstructions of different structures through the implementation of this method that dynamically accommodates variations in the tomographic reconstruction parameters are presented. It is shown both experimentally and theoretically that the depth accuracy of reconstructed APT images is improved using this method. The method requires few parameters in order to be easily usable and substantially improves atom probe tomographic reconstructions of multilayered structures.

Stable amorphous georgeite as a precursor to a high-activity catalyst.

Copper and zinc form an important group of hydroxycarbonate minerals that include zincian malachite, aurichalcite, rosasite and the exceptionally rare and unstable--and hence little known and largely ignored--georgeite. The first three of these minerals are widely used as catalyst precursors for the industrially important methanol-synthesis and low-temperature water-gas shift (LTS) reactions, with the choice of precursor phase strongly influencing the activity of the final catalyst. The preferred phase is usually zincian malachite. This is prepared by a co-precipitation method that involves the transient formation of georgeite; with few exceptions it uses sodium carbonate as the carbonate source, but this also introduces sodium ions--a potential catalyst poison. Here we show that supercritical antisolvent (SAS) precipitation using carbon dioxide (refs 13, 14), a process that exploits the high diffusion rates and solvation power of supercritical carbon dioxide to rapidly expand and supersaturate solutions, can be used to prepare copper/zinc hydroxycarbonate precursors with low sodium content. These include stable georgeite, which we find to be a precursor to highly active methanol-synthesis and superior LTS catalysts. Our findings highlight the value of advanced synthesis methods in accessing unusual mineral phases, and show that there is room for exploring improvements to established industrial catalysts.

Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation.

The BCR-ABL1 fusion gene is a driver oncogene in chronic myeloid leukaemia and 30-50% of cases of adult acute lymphoblastic leukaemia. Introduction of ABL1 kinase inhibitors (for example, imatinib) has markedly improved patient survival, but acquired drug resistance remains a challenge. Point mutations in the ABL1 kinase domain weaken inhibitor binding and represent the most common clinical resistance mechanism. The BCR-ABL1 kinase domain gatekeeper mutation Thr315Ile (T315I) confers resistance to all approved ABL1 inhibitors except ponatinib, which has toxicity limitations. Here we combine comprehensive drug sensitivity and resistance profiling of patient cells ex vivo with structural analysis to establish the VEGFR tyrosine kinase inhibitor axitinib as a selective and effective inhibitor for T315I-mutant BCR-ABL1-driven leukaemia. Axitinib potently inhibited BCR-ABL1(T315I), at both biochemical and cellular levels, by binding to the active form of ABL1(T315I) in a mutation-selective binding mode. These findings suggest that the T315I mutation shifts the conformational equilibrium of the kinase in favour of an active (DFG-in) A-loop conformation, which has more optimal binding interactions with axitinib. Treatment of a T315I chronic myeloid leukaemia patient with axitinib resulted in a rapid reduction of T315I-positive cells from bone marrow. Taken together, our findings demonstrate an unexpected opportunity to repurpose axitinib, an anti-angiogenic drug approved for renal cancer, as an inhibitor for ABL1 gatekeeper mutant drug-resistant leukaemia patients. This study shows that wild-type proteins do not always sample the conformations available to disease-relevant mutant proteins and that comprehensive drug testing of patient-derived cells can identify unpredictable, clinically significant drug-repositioning opportunities.

Al-doped Fe2O3 as a support for molybdenum oxide methanol oxidation catalysts.

We have made high surface area catalysts for the selective oxidation of methanol to formaldehyde. This is done in two ways - (i) by doping haematite with Al ions, to increase the surface area of the material, but which itself is unselective and (ii) by surface coating with Mo which induces high selectivity. Temperature programmed desorption (TPD) of methanol shows little difference in surface chemistry of the doped haematite from the undoped material, with the main products being CO2 and CO, but shifted to somewhat higher desorption temperature. However, when Mo is dosed onto the haematite surface, the chemistry changes completely to show mainly the selective product, formaldehyde, with no CO2 production, and this is little changed up to 10% Al loading. But at 15 wt% Al, the chemistry changes to indicate the presence of a strongly acidic function at the surface, with additional dimethyl ether and CO/CO2 production characteristic of the presence of alumina. Structurally, X-ray diffraction (XRD) shows little change over the range 0-20% Al doping, except for some small lattice contraction, while the surface area increases from around 20 to 100 m2 g-1. Using X-ray absorption spectroscopy (XAS) it is clear that, at 5% loading, the Al is incorporated into the Fe2O3 corundum lattice, which has the same structure as α-alumina. By 10% loading then it appears that the alumina starts to nano-crystallise within the haematite lattice into the γ form. At higher loadings, there is evidence of phase separation into separate Al-doped haematite and γ-alumina. If we add 1 monolayer equivalent of Mo to the surface there is already high selectivity to formaldehyde, but little change in structure, because that monolayer is isolated at the surface. However, when three monolayers equivalent of Mo is added, we then see aluminium molybdate type signatures in the XANES spectra at 5% Al loading and above. These appear to be in a sub-surface layer with Fe molybdate, which we interpret as due to Al substitution into ferric molybdate layers immediately beneath the topmost surface layer of molybdena. It seems like the separate γ-alumina phase is not covered by molybdena and is responsible for the appearance of the acid function products in the TPD.

The electronic structure, surface properties, and in situ N2O decomposition of mechanochemically synthesised LaMnO3.

The use of mechanochemistry to prepare catalytic materials is of significant interest; it offers an environmentally beneficial, solvent-free, route and produces highly complex structures of mixed amorphous and crystalline phases. This study reports on the effect of milling atmosphere, either air or argon, on mechanochemically prepared LaMnO3 and the catalytic performance towards N2O decomposition (deN2O). In this work, high energy resolution fluorescence detection (HERFD), X-ray absorption near edge structure (XANES), X-ray emission, and X-ray photoelectron spectroscopy (XPS) have been used to probe the electronic structural properties of the mechanochemically prepared materials. Moreover, in situ studies using near ambient pressure (NAP)-XPS, to follow the materials during catalysis, and high pressure energy dispersive EXAFS studies, to mimic the preparation conditions, have also been performed. The studies show that there are clear differences between the air and argon milled samples, with the most pronounced changes observed using NAP-XPS. The XPS results find increased levels of active adsorbed oxygen species, linked to the presence of surface oxide vacancies, for the sample prepared in argon. Furthermore, the argon milled LaMnO3 shows improved catalytic activity towards deN2O at lower temperatures compared to the air milled and sol-gel synthesised LaMnO3. Assessing this improved catalytic behaviour during deN2O of argon milled LaMnO3 by in situ NAP-XPS suggests increased interaction of N2O at room temperature within the O 1s region. This study further demonstrates the complexity of mechanochemically prepared materials and through careful choice of characterisation methods how their properties can be understood.

Targeting S-adenosylmethionine biosynthesis with a novel allosteric inhibitor of Mat2A.

S-Adenosyl-L-methionine (SAM) is an enzyme cofactor used in methyl transfer reactions and polyamine biosynthesis. The biosynthesis of SAM from ATP and L-methionine is performed by the methionine adenosyltransferase enzyme family (Mat; EC 2.5.1.6). Human methionine adenosyltransferase 2A (Mat2A), the extrahepatic isoform, is often deregulated in cancer. We identified a Mat2A inhibitor, PF-9366, that binds an allosteric site on Mat2A that overlaps with the binding site for the Mat2A regulator, Mat2B. Studies exploiting PF-9366 suggested a general mode of Mat2A allosteric regulation. Allosteric binding of PF-9366 or Mat2B altered the Mat2A active site, resulting in increased substrate affinity and decreased enzyme turnover. These data support a model whereby Mat2B functions as an inhibitor of Mat2A activity when methionine or SAM levels are high, yet functions as an activator of Mat2A when methionine or SAM levels are low. The ramification of Mat2A activity modulation in cancer cells is also described.

Pd local structure and size correlations to the activity of Pd/TiO2 for photocatalytic reforming of methanol.

The interaction between Pd and TiO2 for promoting photocatalytic activity was investigated by tailoring the size of Pd nanoparticles and monitoring the photocatalytic activity of methanol photo-reforming reaction for hydrogen gas production. We show that at 0.6 wt% Pd loading, the catalyst with highly dispersed nanoparticles obtained at 1 °C temperature exhibits superior photocatalytic activity for hydrogen gas production. At different weights of Pd loading, tailoring two sets of catalysts with different structural properties provides correlation between the changes in the Pd local structures and the rate of hydrogen production. The impact of controlling the structural properties of metal nanoparticles on influencing H2 production outweighs the effect of metal loading variation. The differences of Pd/TiO2 activity at the different metal loadings were correlated with the changes in the Pd local structure consequently affecting the electronic transfer and photocatalytic efficiency.

Intracardiac ablation for atrioventricular nodal reentry tachycardia using a 6 mm distal electrode cryoablation catheter: Prospective, multicenter, North American study (ICY-AVNRT STUDY).

INTRODUCTION: Radiofrequency (RF) ablation is effective for slow pathway ablation, but carries a risk of inadvertent AV block requiring permanent pacing. By comparison, cryoablation with a 4-mm distal electrode catheter has not been reported to cause permanent AV block but has been shown to be less effective than RF ablation. We sought to define the safety and efficacy of a 6-mm distal electrode cryoablation catheter for slow pathway ablation in patients with atrioventricular nodal reentry tachycardia (AVNRT). METHODS AND RESULTS: Twenty-six U.S. and eight Canadian centers participated in the study. Patients with supraventricular tachycardia (SVT) thought likely to be AVNRT were enrolled. If AVNRT was inducible and confirmed to be the clinical SVT, then the slow pathway was targeted with a cryoablation catheter using a standardized protocol of best practices. Acute success was defined as inducibility of no more than one echo beat after cryoablation. Primary efficacy was defined as acute success and the absence of documented recurrent AVNRT over 6 months of follow-up. Primary safety was a composite of serious procedure-related adverse events and/or device-related complications. Note that 397 subjects met enrollment criteria after the EP study and received cryoablation. Mean ablation procedure duration (including a waiting period) was 89 ± 40 minutes, and mean fluoroscopy time was 4.8 ± 5.9 minutes. Isoproterenol was administered before cryoablation in 53% and after the last lesion in 85% of cases. Acute procedural success was realized in 95% (378 of 397) of subjects. No subject received a permanent pacemaker due to AV block. The slow pathway could not be ablated in 19 subjects, including: 12 due to inefficacy, 2 due to transient AV block, and 5 due to both inefficacy and transient AV block. RF ablation was used in the same procedure in 11 of 19 failed subjects, and was ineffective in 3 subjects. Among the group with acute success, 10 subjects (2.7%) had documented recurrent AVNRT over the 6-month follow-up period, and all occurred within 3 months of the index cryoablation. Serious procedure-related adverse events occurred in 4 subjects (1.0%), including one each: tamponade, pulmonary embolism, femoral vein hemorrhage, and diagnostic EP catheter knotting. None of these serious adverse events were related to use of the cryoablation catheter. Overall, 93% of subjects had successful slow pathway ablation at 6 months with the study cryoablation catheter. CONCLUSIONS: Cryoablation for AVNRT using a focal 6-mm catheter was safe and effective. It resulted in a low risk of recurrence over 6 months of follow-up with no incidence of AV block requiring permanent pacing.

Supported metal nanoparticles with tailored catalytic properties through sol-immobilisation: applications for the hydrogenation of nitrophenols.

The use of sol-immobilisation to prepare supported metal nanoparticles is an area of growing importance in heterogeneous catalysis; it affords greater control of nanoparticle properties compared to conventional catalytic routes e.g. impregnation. This work, and other recent studies, demonstrate how the properties of the resultant supported metal nanoparticles can be tailored by adjusting the conditions of colloidal synthesis i.e. temperature and solvent. We further demonstrate the applicability of these methods to the hydrogenation of nitrophenols using a series of tailored Pd/TiO2 catalysts, with low Pd loading of 0.2 wt%. Here, the temperature of colloidal synthesis is directly related to the mean particle diameter and the catalytic activity. Smaller Pd particles (2.2 nm, k = 0.632 min-1, TOF = 560 h-1) perform better than their larger counterparts (2.6 nm, k = 0.350 min-1, TOF = 370 h-1) for the hydrogenation of p-nitrophenol, with the catalyst containing smaller NPs found to have increased stability during recyclability studies, with high activity (>90% conversion after 5 minutes) maintained across 5 catalytic cycles.

Structural behaviour of copper chloride catalysts during the chlorination of CO to phosgene.

The interaction of CO with an attapulgite-supported Cu(ii)Cl2 catalyst has been examined in a micro-reactor arrangement. CO exposure to the dried, as-received catalyst at elevated temperatures leads to the formation of CO2 as the only identifiable product. However, phosgene production can be induced by using a catalyst pre-treatment where the supported Cu(ii)Cl2 sample is exposed to a diluted stream of chlorine. Subsequent CO exposure at ∼370 °C then leads to phosgene production. In order to investigate the origins of this atypical set of reaction characteristics, a series of X-ray absorption experiments were performed that were supplemented by DFT calculations. XANES measurements establish that at the elevated temperatures connected with phosgene formation, the catalyst is comprised of Cu+ and a small amount of Cu2+. Moreover, the data show that unique to the chlorine pre-treated sample, CO exposure at elevated temperature results in a short-lived oxidation of the copper. On the basis of calculated CO adsorption energies, DFT calculations indicate that a mixed Cu+/Cu2+ catalyst is required to support CO chemisorption.

The adsorption of Cu on the CeO2(110) surface.

We report a detailed density functional theory (DFT) study in conjunction with extended X-ray absorption fine structure (EXAFS) experiments on the geometrical and local electronic properties of Cu adatoms and Cu(ii) ions in presence of water molecules and of CuO nanoclusters on the CeO2(110) surface. Our study of (CuO)n(=1,2&4) clusters on CeO2(110) shows that based on the Cu-O environment, the geometrical properties of these clusters may vary and their presence may lead to relatively high localization of charge on the exposed surfaces. We find that in the presence of an optimum concentration of water molecules, Cu has a square pyramidal geometry, which agrees well with our experimental findings; we also find that Cu(ii) facilitates water adsorption on the CeO2(110) surface. We further show that a critical concentration of water molecules is required for the hydrolysis of water on Cu(OH)2/CeO2(110) and on pristine CeO2(110) surfaces.

Enzyme Activity by Design: An Artificial Rhodium Hydroformylase for Linear Aldehydes.

Artificial metalloenzymes (ArMs) are hybrid catalysts that offer a unique opportunity to combine the superior performance of natural protein structures with the unnatural reactivity of transition-metal catalytic centers. Therefore, they provide the prospect of highly selective and active catalytic chemical conversions for which natural enzymes are unavailable. Herein, we show how by rationally combining robust site-specific phosphine bioconjugation methods and a lipid-binding protein (SCP-2L), an artificial rhodium hydroformylase was developed that displays remarkable activities and selectivities for the biphasic production of long-chain linear aldehydes under benign aqueous conditions. Overall, this study demonstrates that judiciously chosen protein-binding scaffolds can be adapted to obtain metalloenzymes that provide the reactivity of the introduced metal center combined with specifically intended product selectivity.

Probing the Role of a Non-Thermal Plasma (NTP) in the Hybrid NTP Catalytic Oxidation of Methane.

Three recurring hypotheses are often used to explain the effect of non-thermal plasmas (NTPs) on NTP catalytic hybrid reactions; namely, modification or heating of the catalyst or creation of new reaction pathways by plasma-produced species. NTP-assisted methane (CH4 ) oxidation over Pd/Al2 O3 was investigated by direct monitoring of the X-ray absorption fine structure of the catalyst, coupled with end-of-pipe mass spectrometry. This in situ study revealed that the catalyst did not undergo any significant structural changes under NTP conditions. However, the NTP did lead to an increase in the temperature of the Pd nanoparticles; although this temperature rise was insufficient to activate the thermal CH4 oxidation reaction. The contribution of a lower activation barrier alternative reaction pathway involving the formation of CH3 (g) from electron impact reactions is proposed.

Fetal oxidative stress mechanisms of neurodevelopmental deficits and exacerbation by ethanol and methamphetamine.

In utero exposure of mouse progeny to alcohol (ethanol, EtOH) and methamphetamine (METH) causes substantial postnatal neurodevelopmental deficits. One emerging pathogenic mechanism underlying these deficits involves fetal brain production of reactive oxygen species (ROS) that alter signal transduction, and/or oxidatively damage cellular macromolecules like lipids, proteins, and DNA, the latter leading to altered gene expression, likely via non-mutagenic mechanisms. Even physiological levels of fetal ROS production can be pathogenic in biochemically predisposed progeny, and ROS formation can be enhanced by drugs like EtOH and METH, via activation/induction of ROS-producing NADPH oxidases (NOX), drug bioactivation to free radical intermediates by prostaglandin H synthases (PHS), and other mechanisms. Antioxidative enzymes, like catalase in the fetal brain, while low, provide critical protection. Oxidatively damaged DNA is normally rapidly repaired, and fetal deficiencies in several DNA repair proteins, including oxoguanine glycosylase 1 (OGG1) and breast cancer protein 1 (BRCA1), enhance the risk of drug-initiated postnatal neurodevelopmental deficits, and in some cases deficits in untreated progeny, the latter of which may be relevant to conditions like autism spectrum disorders (ASD). Risk is further regulated by fetal nuclear factor erythroid 2-related factor 2 (Nrf2), a ROS-sensing protein that upregulates an array of proteins, including antioxidative enzymes and DNA repair proteins. Imbalances between conceptal pathways for ROS formation, versus those for ROS detoxification and DNA repair, are important determinants of risk. Birth Defects Research (Part C) 108:108-130, 2016. © 2016 Wiley Periodicals, Inc.

Design and stabilisation of a high area iron molybdate surface for the selective oxidation of methanol to formaldehyde.

The performance of Mo-enriched, bulk ferric molybdate, employed commercially for the industrially important reaction of the selective oxidation of methanol to formaldehyde, is limited by a low surface area, typically 5-8 m(2) g(-1). Recent advances in the understanding of the iron molybdate catalyst have focused on the study of MoOx@Fe2O3 (MoOx shell, Fe2O3 core) systems, where only a few overlayers of Mo are present on the surface. This method of preparing MoOx@Fe2O3 catalysts was shown to support an iron molybdate surface of higher surface area than the industrially-favoured bulk phase. In this research, a MoOx@Fe2O3 catalyst of even higher surface area was stabilised by modifying a haematite support containing 5 wt% Al dopant. The addition of Al was an important factor for stabilising the haematite surface area and resulted in an iron molybdate surface area of ∼35 m(2) g(-1), around a 5 fold increase on the bulk catalyst. XPS confirmed Mo surface-enrichment, whilst Mo XANES resolved an amorphous MoOx surface monolayer supported on a sublayer of Fe2(MoO4)3 that became increasingly extensive with initial Mo surface loading. The high surface area MoOx@Fe2O3 catalyst proved amenable to bulk characterisation techniques; contributions from Fe2(MoO4)3 were detectable by Raman, XAFS, ATR-IR and XRD spectroscopies. The temperature-programmed pulsed flow reaction of methanol showed that this novel, high surface area catalyst (3ML-HSA) outperformed the undoped analogue (3ML-ISA), and a peak yield of 94% formaldehyde was obtained at ∼40 °C below that for the bulk Fe2(MoO4)3 phase. This work demonstrates how core-shell, multi-component oxides offer new routes for improving catalytic performance and understanding catalytic activity.

The adsorbed state of a thiol on palladium nanoparticles.

In the present work, a combination of imaging, spectroscopic and computational methods shows that 1-dodecanethiol undergoes S-deprotonation to form 1-dodecanethiolate on the surface of palladium nanoparticles, which then self-assembles into a structure that shows a high degree of order. The alkyl chain is largely in the all-trans conformation, which occurs despite the small size of the nanoparticle, (mean diameter = 3.9 nm). Inelastic neutron scattering spectroscopy is readily able to characterise organic surface layers on nanoparticles; the nature of the material is irrelevant: whether the nanoparticle core is an oxide, a metal or a semiconductor makes no difference. Comparison to DFT calculations allows insights into the nature and conformation of the adsorbed layer.

Deficient DNA repair exacerbates ethanol-initiated DNA oxidation and embryopathies in ogg1 knockout mice: gender risk and protection by a free radical spin trapping agent.

Reactive oxygen species (ROS) have been implicated in the teratogenicity of alcohol (ethanol, EtOH). To determine the involvement of embryonic oxidative DNA damage, DNA repair-deficient oxoguanine glycosylase 1 (ogg1) knockout embryos were exposed in culture to EtOH (2 or 4 mg/ml), with or without pretreatment with the free radical spin trap phenylbutylnitrone (PBN) (0.125 mM). Visceral yolk sacs were used to genotype embryos for DNA repair status and gender. EtOH caused a concentration-dependent decrease in anterior neuropore closure (ANPC), somite development, turning, crown-rump length (CRL), yolk sac diameter (YSD) and head length (HL) (p < 0.001) in all 3 ogg1 genotypes. There was a further ogg1 gene dose-dependent decrease from +/+ to -/- embryos in ANPC, somite development, turning, CRL and HL (p < 0.05), and a gene-dependent correlation between HL and ANPC (p < 0.01). Female embryos exhibited lesser ANPC and turning than males (p < 0.05), suggesting underlying gender-dependent target-specific determinants. PBN pretreatment increased ANPC, somite development, turning, CRL, YSD and HL (p < 0.001), although this protection against EtOH was slightly less effective in -/- embryos. Oxidatively damaged DNA determined as 8-oxo-2'-deoxyguanosine (8-oxodGuo), which is repaired by OGG1, was measured in single embryos in vivo after maternal EtOH treatment (4 g/kg i.p). EtOH increased embryonic 8-oxodGuo in an ogg1 gene-dependent fashion, with the highest levels in -/- embryos. These results show that embryonic DNA repair status and gender are determinants of risk. ROS-initiated embryonic DNA oxidation is involved in EtOH embryopathies.

Enhanced NADPH oxidases and reactive oxygen species in the mechanism of methanol-initiated protein oxidation and embryopathies in vivo and in embryo culture.

Methanol (MeOH) teratogenicity in rodents may be mediated in part by reactive oxygen species (ROS), the source of which is unknown. To determine if MeOH enhances embryonic ROS-producing NADPH oxidases (NOXs), p22phox mRNA and protein and oxidatively damaged protein were measured in gestational day 12 MeOH-exposed CD-1 mouse embryos with or without pretreatment with the free radical spin trap phenylbutylnitrone (PBN) or the NOX inhibitor diphenyleneiodonium chloride (DPI). MeOH exposure upregulated p22phox mRNA and protein expression, and enhanced protein oxidation, within 3-6 h. Compared to embryos exposed to MeOH alone, PBN and DPI pretreatment decreased MeOH-enhanced p22phox mRNA expression, DPI but not PBN blocked p22phox protein expression, and both blocked protein oxidation. To assess developmental relevance, mouse embryos were exposed in culture for 24 h to MeOH or vehicle with or without pretreatment with PBN, DPI, or the prostaglandin H synthase (PHS) inhibitor eicosatetraynoic acid (ETYA), and evaluated for abnormalities. ETYA did not prevent MeOH embryopathies, despite blocking phenytoin embryopathies (ROS-initiating positive control), precluding bioactivation of MeOH or its metabolites by PHS. Concentration-dependent MeOH embryopathies were blocked by both DPI and PBN pretreatment, suggesting that enhanced embryonic NOX-catalyzed ROS formation and oxidative stress may contribute to the mechanism of MeOH embryopathies.

Embryonic catalase protects against ethanol embryopathies in acatalasemic mice and transgenic human catalase-expressing mice in embryo culture.

Reactive oxygen species (ROS) have been implicated in the mechanism of ethanol (EtOH) teratogenicity, but the protective role of the embryonic antioxidative enzyme catalase is unclear, as embryonic activity is only about 5% of maternal levels. We addressed this question in a whole embryo culture model. C57BL/6 mouse embryos expressing human catalase (hCat) or their wild-type (C57BL/6 WT) controls, and C3Ga.Cg-Cat(b)/J catalase-deficient, acatalasemic (aCat) mouse embryos or their wild-type C3HeB/FeJ (C3H WT) controls, were explanted on gestational day (GD) 9 (plug=GD 1), exposed for 24h to 2 or 4mg/mL EtOH or vehicle, and evaluated for functional and morphological changes. hCat and C57BL/6 WT vehicle-exposed embryos developed normally, while EtOH was embryopathic in C57BL/6 WT embryos, evidenced by decreases in anterior neuropore closure, somites developed, turning and head length, whereas hCat embryos were protected (p<0.001). Maternal pretreatment of C57BL/6 WT dams with 50kU/kg PEG-catalase (PEG-cat) 8h prior to embryo culture, which increases embryonic catalase activity, blocked all EtOH embryopathies (p<0.001). Vehicle-exposed aCat mouse embryos had lower yolk sac diameters compared to WT controls, suggesting that endogenous ROS are embryopathic. EtOH was more embryopathic in aCat embryos than WT controls, evidenced by reduced head length and somite development (p<0.01), and trends for reduced anterior neuropore closure, turning and crown-rump length. Maternal pretreatment of aCat dams with PEG-Cat blocked all EtOH embryopathies (p<0.05). These data suggest that embryonic catalase is a determinant of risk for EtOH embryopathies.