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Bohn B.,Julich Research Center | Zetzsch C.,University of Bayreuth | Zetzsch C.,Fraunhofer Institute for Toxicology and Experimental Medicine
Physical Chemistry Chemical Physics

The reversible gas-phase addition of OH radicals to the trimethylbenzenes was investigated in pulsed experiments utilizing VUV flash-photolysis resonance-fluorescence of H2O in the temperature range of 275-340 K. Triexponential OH decays were observed in the presence of the trimethylbenzenes, indicating the participation of more than one adduct species. Analytical solutions for the system of differential equations with two adduct isomers were derived, and the OH decay curves were evaluated based on this reaction model. This led to significant improvements of fit qualities and notable changes in OH rate constants compared to a previous model with a single adduct species. The detailed analysis was confined to 1,3,5-trimethylbenzene where reversible formation of two OH-aromatic ortho- and ipso-adduct isomers is feasible in accordance with the extended reaction model. Only after inclusion of additional isomerization reactions, consistent thermochemical data were obtained from the fitted rate constants. Reaction enthalpies of -83 ± 7 kJ mol-1 and -35 ± 22 kJ mol-1 were derived for the formation of one adduct isomer and the isomerization into the other, respectively. Based on literature data, the more and less stable adducts were assigned to ipso- and ortho-adduct isomers, respectively. The potential isomerization precluded the determination of primary yields of adduct isomers but formation of the ipso-adduct in any case is a minor process. For the rate constants of the OH + 1,3,5-trimethylbenzene reaction an Arrhenius expression kOH = 1.32 × 10-11 cm3 s-1 exp(450 ± 50 K/T) was obtained. Based on the same approach, the rate constants of the OH reactions with 1,2,3-trimethylbenzene and 1,2,4-trimethylbenzene were derived as k OH = 3.61 × 10-12 cm3 s-1 exp(620 ± 80 K/T) and kOH = 2.73 × 10-12 cm3 s-1 exp(730 ± 70 K/T), respectively. This journal is © the Owner Societies. Source

Mueller A.N.,Max Planck Institute for Terrestrial Microbiology | Ziemann S.,Max Planck Institute for Terrestrial Microbiology | Treitschke S.,Max Planck Institute for Terrestrial Microbiology | Treitschke S.,Fraunhofer Institute for Toxicology and Experimental Medicine | And 2 more authors.
PLoS Pathogens

The basidiomycete Ustilago maydis causes smut disease in maize, with large plant tumors being formed as the most prominent disease symptoms. During all steps of infection, U. maydis depends on a biotrophic interaction, which requires an efficient suppression of plant immunity. In a previous study, we identified the secreted effector protein Pit2, which is essential for maintenance of biotrophy and induction of tumors. Deletion mutants for pit2 successfully penetrate host cells but elicit various defense responses, which stops further fungal proliferation. We now show that Pit2 functions as an inhibitor of a set of apoplastic maize cysteine proteases, whose activity is directly linked with salicylic-acid-associated plant defenses. Consequently, protease inhibition by Pit2 is required for U. maydis virulence. Sequence comparisons with Pit2 orthologs from related smut fungi identified a conserved sequence motif. Mutation of this sequence caused loss of Pit2 function. Consequently, expression of the mutated protein in U. maydis could not restore virulence of the pit2 deletion mutant, indicating that the protease inhibition by Pit2 is essential for fungal virulence. Moreover, synthetic peptides of the conserved sequence motif showed full activity as protease inhibitor, which identifies this domain as a new, minimal protease inhibitor domain in plant-pathogenic fungi. © 2013 Mueller et al. Source

Hoymann H.G.,Fraunhofer Institute for Toxicology and Experimental Medicine
Frontiers in Pharmacology

The ICH guideline S7A requires safety pharmacology tests including measurements of pulmonary function. In the first step-as part of the "core battery" - lung function tests in conscious animals are requested. If potential adverse effects raise concern for human safety, these should be explored in a second step as a "follow-up study." For these two stages of safety pharmacology testing, both non-invasive and invasive techniques are needed which should be as precise and reliable as possible. A short overview of typical in vivo measurement techniques is given, their advantages and disadvantages are discussed and out of these the non-invasive head-out body plethysmography and the invasive but repeatable body plethysmography in orotracheally intubated rodents are presented in detail. For validation purposes the changes in the respective parameters such as tidal midexpiratory flow (EF50) or lung resistance have been recorded in the same animals in typical bronchoconstriction models and compared. In addition, the technique of head-out body plethysmography has been shown to be useful to measure lung function in juvenile rats starting from day two of age. This allows safety pharmacology testing and toxicological studies in juvenile animals as a model for the young developing organism as requested by the regulatory authorities (e.g., EMEA Guideline 1/2008). It is concluded that both invasive and non-invasive pulmonary function tests are capable of detecting effects and alterations on the respiratory system with different selectivity and area of operation. The use of both techniques in a large number of studies in mice and rats in the last years have demonstrated that they provide useful and reliable information on pulmonary mechanics in safety pharmacology and toxicology testing, in investigations of respiratory disorders, and in pharmacological efficacy studies. © 2012 Hoymann. Source

Buschmann J.,Fraunhofer Institute for Toxicology and Experimental Medicine
Methods in Molecular Biology

In many countries the process of toxicity testing of environmental chemicals is ruled by a framework of OECD guidelines. The present paper will give an overview over the relevant OECD guidelines and guidance documents and mainly focus on methodological issues related to the prenatal toxicity testing guideline. Relevant guideline text will be provided, and practical recommendations will be given both for critical issues of experimental methodology and data interpretation. © 2013 Springer Science+Business Media, LLC. Source

Creutzenberg O.,Fraunhofer Institute for Toxicology and Experimental Medicine
Archives of Toxicology

After deposition in the respiratory tract, nanoparticles exhibit acute, neutrophil-driven inflammatory and oxidative reactions, fibrotic responses and in chronic studies under overload conditions carcinogenic effects, more severely than the microscaled materials of the same chemistry. Besides these effects also known to be induced by microsized particles, nanoparticles principally can translocate from the site of exposure to circulation and become systemically available. This may either increase the toxic outcome (e.g. cardio-vascular effects and potential responses in remote organs) or facilitate an elimination of nanomaterials. For example, in combination with partial dissolution, a strong lung response after a short-term inhalative exposure may be followed by a rapid recovery effect. Mechanistically, in vitro and in vivo tests demonstrated that nanoparticles induce inflammation and oxidative stress after interaction with macrophages and lung epithelial cells; consequently, a cytotoxic and genotoxic potential may exist. The deposition, retention and clearance behaviour of inhaled nanomaterials and the toxic effects observed are decisively dependent on the particle agglomeration status of the aerosol. Two principally different experimental approaches are used for inhalative exposure to nanoparticles: either (1) a basic research-oriented approach using very small aerosol mass concentrations or particle formulations that result in at least partially nanoscaled aerosols; in this way, the potential hazard and the translocation potential for individual nanoparticles can be followed effectively; or (2) exposure scenarios mimicking the occupational situation (risk-oriented) with mostly agglomerated nanoparticles; consequently, the probable risk deriving from incidental/accidental exposure can be assessed more adequately. © Springer-Verlag 2012. Source

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