Al-26-Mg-26 ages of iron meteorites

An exposure age for an iron meteorite can be calculated from measurements of a radioactive nuclide and a stable nuclide that are produced by similar sets of nuclear reactions, provided that the stable nuclide is present with low initial abundance. The standard methods rely on either K-40 (t(sub 1/2) = 1.26 Gy), K-39, and K-41 or on a shorter-lived radionuclide and a stable, noble gas isotope. Widely used pairs of this type include Cl-36/Ar-36 and Al-26/Ne-21. Other pairs that may serve the purpose for iron meteorites contain many stable isotopes besides those of K and the noble gases that are produced partly by cosmic rays. We consider here the calculation of exposure ages, t(sub 26), from measurements of Al-26 (t(sub 1/2) = 0.7 My) and (stable) Mg-26. Ages based on Al-26/Mg-26 ratios, like those based on Cl-36/Ar-36 ratios, are 'buffered' against changes in relative production rates due to shielding because decay of the radioactive nuclide accounts for a good part of the inventory of the stable nuclide

Neutrophil Extracellular Traps Directly Induce Epithelial and Endothelial Cell Death: A Predominant Role of Histones

Neutrophils play an important role in innate immunity by defending the host organism against invading microorganisms. Antimicrobial activity of neutrophils is mediated by release of antimicrobial peptides, phagocytosis as well as formation of neutrophil extracellular traps (NET). These structures are composed of DNA, histones and granular proteins such as neutrophil elastase and myeloperoxidase. This study focused on the influence of NET on the host cell functions, particularly on human alveolar epithelial cells as the major cells responsible for gas exchange in the lung. Upon direct interaction with epithelial and endothelial cells, NET induced cytotoxic effects in a dose-dependent manner, and digestion of DNA in NET did not change NET-mediated cytotoxicity. Pre-incubation of NET with antibodies against histones, with polysialic acid or with myeloperoxidase inhibitor but not with elastase inhibitor reduced NET-mediated cytotoxicity, suggesting that histones and myeloperoxidase are responsible for NET-mediated cytotoxicity. Although activated protein C (APC) did decrease the histone-induced cytotoxicity in a purified system, it did not change NET-induced cytotoxicity, indicating that histone-dependent cytotoxicity of NET is protected against APC degradation. Moreover, in LPS-induced acute lung injury mouse model, NET formation was documented in the lung tissue as well as in the bronchoalveolar lavage fluid. These data reveal the important role of protein components in NET, particularly histones, which may lead to host cell cytotoxicity and may be involved in lung tissue destruction

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

Biorelevant in vitro dissolution testing of products containing micronized or nanosized fenofibrate with a view to predicting plasma profiles

The ability of in vitro biorelevant dissolution tests to predict the in vivo performance of nanosized fenofibrate (Lipidil 145 ONE®) and microsized fenofibrate (Lipidil - Ter®) was evaluated in this study. In vitro dissolution was carried out using USP apparatus 2 (paddle method) with updated biorelevant media to simulate the pre- and postprandial states. Membrane filters with different pore sizes were evaluated for their ability to hold back undissolved, nanosized drug particles. It was shown that filters with pore sizes of 0.1 μm and 0.02 μm were able to separate molecularly dissolved drug from colloidal and undissolved particles. In vitro results obtained with a suitable filter were used to generate simulated plasma profiles in combination with two different models using STELLA® software: (a) under the assumption of no permeability restrictions to absorption and (b) under the assumption of a permeability restriction. The simulated plasma profiles were compared to in vivo data for the nanosized and the microsized formulation in the fasted and fed states. The first model approach resulted in good correlation for the microsized fenofibrate formulation, but the plasma profile of the formulation containing nanosized fenofibrate was overpredicted in the fasted state. The second model successfully correlated with in vivo data for both formulations, regardless of prandial state. Comparison of simulations with the two models indicates that in the fasted state, absorption of fenofibrate from the nanosized formulation is at least partly permeability-limited, while for the microsized formulation the dissolution of fenofibrate appears to be rate-determining. © 2010 Elsevier Inc. All rights reserved