Development and Evaluation of a Nanoparticle Generator for Human Inhalation Studies with Airborne Zinc Oxide

In the EU there is an increasing need for regulatory agencies to derive health based threshold limits based on human inhalation studies with airborne particles. A necessary prerequisite for such projects is the development of a suitable generator system to produce nanoparticle test aerosols for human whole-body inhalation studies. We decided to use a generator with flame-based heating of aqueous precursor solutions. Validation of the test system was done by generating zinc oxide (ZnO) nanoparticles with minimal contamination of trace gases, i.e., nitric oxides or carbon monoxide that could confound the effects seen in exposed subjects. ZnO was selected based on the uncertainties surrounding its health effects after exposure at the workplace. The generation process of the developed flame generator yields ZnO nanoparticles with monomodal size distribution and very good temporal stability. The maximum target exposure mass concentration of 2 mg/m³ ZnO, with a resulting median particle diameter of 57 nm, is attainable in our human exposure laboratory. The morphological examination shows typical agglomerates and aggregates formed by high temperature processes. Overall, the performed experiments confirm that a constant exposure can be provided for all subjects at all times.

Copyright 2014 American Association for Aerosol Research     

Zur Umkupplung von 4-Arylazo-2-pyrazolin-5-onen mit p-Chinondiiminkationen

Recoupling of 4-Arylazo-2-pyrazoline-5-ones with p-Quinonediimine Cations 4-Arylazo-2-pyrazoline-5-ones ( 1a – j ) readily undergo coupling reaction with p-quinonediimine cations ( 2a , b ) to form azomethin dyes ( 3a , b ). The dependence of the rate constants k_K of the dye formation on the substituents of 1a – j as well as on the ionic strength show that the rate-determining step of the coupling reaction is the formation of the intermediate 4 in a bimolecular reaction between the carbanions of 1a – j and p-quinonediimine ( 2a , b ). It became evident that the benzenediazoniumion ( 5a – j ) is eliminated in the reaction of 4 to 3a , b . Under the coupling conditions used, substituted benzene is formed in the reduction reaction of 5a , b by the p-phenylendiamine ( 7a , b ) or by the leuco dye ( 6a , b ).     

Bivalent EGFR-Targeting DARPin-MMAE Conjugates

Epidermal growth factor receptor (EGFR) is a validated tumor marker overexpressed in various cancers such as squamous cell carcinoma (SSC) of the head and neck and gliomas. We constructed protein-drug conjugates based on the anti-EGFR Designed Ankyrin Repeat Protein (DARPin) E01, and compared the bivalent DARPin dimer (DD1) and a DARPin-Fc (DFc) to the monomeric DARPin (DM) and the antibody derived scFv425-Fc (scFvFc) in cell culture and a mouse model. The modular conjugation system, which was successfully applied for the preparation of protein-drug and -dye conjugates, uses bio-orthogonal protein-aldehyde generation by the formylglycine-generating enzyme (FGE). The generated carbonyl moiety is addressed by a bifunctional linker with a pyrazolone for a tandem Knoevenagel reaction and an azide for strain-promoted azide-alkyne cycloaddition (SPAAC). The latter reaction with a PEGylated linker containing a dibenzocyclooctyne (DBCO) for SPAAC and monomethyl auristatin E (MMAE) as the toxin provided the stable conjugates DD1-MMAE (drug-antibody ratio, DAR = 2.0) and DFc-MMAE (DAR = 4.0) with sub-nanomolar cytotoxicity against the human squamous carcinoma derived A431 cells. In vivo imaging of Alexa Fluor 647-dye conjugates in A431-xenografted mice bearing subcutaneous tumors as the SCC model revealed unspecific binding of bivalent DARPins to the ubiquitously expressed EGFR. Tumor-targeting was verified 6 h post-injection solely for DD1 and scFvFc. The total of four administrations of 6.5 mg/kg DD1-MMAE or DFc-MMAE twice weekly did not cause any sequela in mice. MMAE conjugates showed no significant anti-tumor efficacy in vivo, but a trend towards increased necrotic areas (p = 0.2213) was observed for the DD1-MMAE (n = 5).     

Infrarotspektroskopischer (IR) Nachweis von gelöstem Wasser in abgeschreckten Schlacken (Modellsysteme Na2O · P2O5 und Na2O · 2 B2O3)

Inf rarotspektroskopie von Wasser in Schlacken. Chemischer Bindungszustand von Wasser in Schlacken, Abhängigkeit der integralen Extinktion der OH-Banden vom Wasserdampfpartialdruck. Wasserstoff beim ESU-Verfahren.     

Ein Beitrag zur Biosynthese amylosereicher Erbsenstärken

Contribution to the Biosynthesis of High-amylose Pea Starches Biosynthesis of starch is a complex process but few details are still unknown. This paper describes an investigation upon pea starch biosynthesis. Peas as a source of starch offer two qualities, a pea starch with 40% amylose content (smooth pea starch) and a pea starch with more than 60% amylose content (wrinkled pea starch). Samples for analysis were taken during growth. According to the quantitative determination of starch and amylose the accuracy of amylose detection was tested. Furthermore a qualitative analysis was carried out by molecular weight estimation of the starch. Both kinds of peas showed a high amylose synthesis during the last few days of growth, whereas amylopectin synthesis was highly in earlier stages. Wrinkled peas have shown only little synthesis activity of amylopectin during maturity. Therefore the amylose content of these peas was higher, instead of equal amylose synthesis quotas of both smooth and wrinkled peas.     

Non-fickian diffusion with reaction in glassy polymers with swelling induced by the penetrant—effects of consecutive and parallel reactions

A mathematical model is presented for non-Fickian diffusion of a penetrant A into a granular glassy polymer containing a reactive group B, resulting in the desired product P. Further, both a consecutive reaction between A and P (producing X) and a parallel reaction between A and C (producing Y) are incorporated, with C initially present in the particle. The swelling of the polymer, induced by the penetrant, is described by power-law kinetics for the velocity of the swelling front. Kinetics are considered to be first order in each of the two reactants. Concentration profiles in the particle and selectivity to desired product are calculated as function of the swelling behavior of the polymer grain. In case of a consecutive reaction the local concentration of P reaches a maximum value independent of the swelling rate. However, the position of the maximal concentration of P moves towards the center of the grain with a rate depending on the kinetics of swelling. For Case II diffusion this velocity equals the velocity of the advancing front between glassy and rubbery polymer. The selectivity of the desired reaction decreases with decreasing swelling rate. A low swelling rate also results in an inhomogeneous product distribution within the granule. A criterion is derived predicting under what conditions the consecutive reaction can be neglected and a pure product is obtained. The analysis further reveals that both a more homogeneous product and a higher selectivity toward a desired product can be obtained by realizing preswelling of the polymer with an inert swelling agent. For Case II diffusion the concentration profiles of the side product of the parallel reaction, Y, are flat in the rubbery part of the polymer. This is caused by the relatively low swelling rate allowing Y to redistribute in the swollen polymer. If additional C is continuously supplied from the gas phase, then the selectivity decreases continuously with increasing conversion of B.     

Untersuchungen zur Amylosebestimmung in proteinreichen Stärkerohstoffen,insbesondere Erbsen

Investigations on the Amylose Determination in High Protein Starch Source Materials, Especially Peas. The proposed utilization of amylose rich starches requires different methods of amylose determination. In addition to laboratory methods also simple tests are important to that. Because the discussed legume starches are hardly investigated, first of all the suitability of the amperometric iodine titration had to be checked. Then a more easier work was described. In the case of routine analyses a modified test procedure was compared with the method of iodine titration.     

Shale gas pad development planning under price uncertainty

In this article, we study shale gas pad development under natural gas price uncertainty. We optimize the sequence of operations, gas curtailment, and storage on a single pad to maximize the net present value. The optimization problem is formulated as an mixed-integer linear programming model, which is similar to the one proposed by Ondeck et al. We investigate how natural gas price uncertainty affects the operation strategy in the pad development. Both two-stage and multistage stochastic programming are used as the mathematical framework to hedge against uncertainty. Our case study shows that there is value of using stochastic programming when the price variance is high. However, when the variance of the price is low, solving the stochastic programming problems does not create additional value compared with solving the deterministic problem.     

Genetic Deficiency and Pharmacological Stabilization of Mast Cells Ameliorate Pressure Overload-Induced Maladaptive Right Ventricular Remodeling in Mice

Although the response of the right ventricle (RV) to the increased afterload is an important determinant of the patient outcome, very little is known about the underlying mechanisms. Mast cells have been implicated in the pathogenesis of left ventricular maladaptive remodeling and failure. However, the role of mast cells in RV remodeling remains unexplored. We subjected mast cell-deficient WBB6F1-KitW/W-v (Kit^W/Kit^W-v) mice and their mast cell-sufficient littermate controls (MC^+/+) to pulmonary artery banding (PAB). PAB led to RV dilatation, extensive myocardial fibrosis, and RV dysfunction in MC^+/+ mice. In PAB Kit^W/Kit^W-v mice, RV remodeling was characterized by minimal RV chamber dilatation and preserved RV function. We further administered to C57Bl/6J mice either placebo or cromolyn treatment starting from day 1 or 7 days after PAB surgery to test whether mast cells stabilizing drugs can prevent or reverse maladaptive RV remodeling. Both preventive and therapeutic cromolyn applications significantly attenuated RV dilatation and improved RV function. Our study establishes a previously undescribed role of mast cells in pressure overload-induced adverse RV remodeling. Mast cells may thus represent an interesting target for the development of a new therapeutic approach directed specifically at the heart.