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Autophagy refers to a set of catabolic pathways that together facilitate degradation of superfluous, damaged and toxic cellular components. The most studied type of autophagy, called macroautophagy, involves membrane mobilisation, cargo engulfment and trafficking of the newly formed autophagic vesicle to the recycling organelle, the lysosome. Macroautophagy responds to a variety of intra- and extra-cellular stress conditions including, but not limited to, pathogen intrusion, oxygen or nutrient starvation, proteotoxic and organelle stress, and elevation of reactive oxygen species (ROS). ROS are highly reactive oxygen molecules that can interact with cellular macromolecules (proteins, lipids, nucleic acids) to either modify their activity or, when released in excess, inflict irreversible damage. Although increased ROS release has long been recognised for its involvement in macroautophagy activation, the underlying mechanisms and the wider impact of ROS-mediated macroautophagy stimulation remain incompletely understood. We therefore discuss the growing body of evidence that describes the variety of mechanisms modulated by ROS that trigger cytoprotective detoxification via macroautophagy. We outline the role of ROS in signalling upstream of autophagy initiation, by increased gene expression and post-translational modifications of transcription factors, and in the formation and nucleation of autophagic vesicles by cysteine modification of conserved autophagy proteins including ATG4B, ATG7 and ATG3. Furthermore, we review the effect of ROS on selective forms of macroautophagy, specifically on cargo recognition by autophagy receptor proteins p62 and NBR1 (neighbour of BRCA1) and the recycling of mitochondria (mitophagy), and peroxisomes (pexophagy). Finally, we highlight both, the standalone and mutual contributions of abnormal ROS signalling and macroautophagy to the development and progression of neurodegenerative diseases., Graphical abstract Image 1, Highlights • ROS are messengers that modify protein activity by PTMs. • ROS-mediated PTMs regulate activity and specificity of autophagy proteins. • Increase in autophagy mediates rapid clearance of oxidised cargo and ROS sources. • The importance of ROS-mediated autophagy is highlighted in neurodegeneration.

To mitigate harmful algae blooms, chemicals are applied to the water that immobilize phosphate through adsorption. Metal-organic frameworks (MOFs) have recently emerged as a promising class of solid adsorbents for a wide variety of water pollutants, including phosphate. In the context of algae blooms however, limited knowledge exists regarding the performance of low-cost MOFs, their chemical stability in dilute phosphate concentrations and how they compare to other types of commonly used adsorbents. In this study, three iron based and low-cost MOFs were compared against commercial adsorbents in a relevant context. Overall, the MOFs exhibited a superior performance in terms of kinetics and adsorption capacity over a wide range of concentrations. The examination of the pore structure data revealed direct correlations with the adsorption kinetics. The comparison of the material cost and the adsorption capacity at ultra-low concentrations places these MOFs in a position to compete against commercial adsorbents. The exposure of the MOFs to dilute phosphate solutions resulted in negligible linker losses.

A series of C-21 mercapto derivatives of hydrocortisone have been synthesized and evaluated in cell based transrepression and transactivation assays. The benzothiazole derivative, compound 6 not only showed a dissociated profile in vitro functional assays but also a pharmacological profile in a Brown-Norway rat therapeutic index model of asthma that dissociated side effects (thymolysis) while maintaining efficacy against pulmonary inflammation and lung function.

This study is designed to explore the impact of peer mentoring on end-of-life decision making.A controlled randomized intervention study with 203 patients from 21 dialysis centers across Michigan explored the impact of peer mentors, dialysis patients trained to help other patients, on end-of-life planning.Communicating information on advance directives (ADs) through peer mentoring significantly influenced the completion of ADs overall compared with distributing standard printed material or no specific designed intervention. However, the influence was most prominent among African Americans, not only increasing actual completion of ADs (P0.001) and comfort discussing ADs (P0.01), but also improving subjective well-being (P0.05) and anxiety (P0.05) during the study period. These effects of peer mentoring did not appear among white patients, although printed material on ADs decreased reported suicidal ideation (P0.05).These results suggest the importance of addressing specific cultural factors in the process of AD education. Common practice assumes that printed materials are effective in educating patients about health care and decision making. However, peer mentoring, a relationship-centered person-to-person approach, may be more effective in some cultural groups because it partakes of oral, rather than written, traditions. Acknowledging cultural differences and tailoring our approach could be powerful in enhancing trust and participation and decreasing potential disparities in health care outcomes.

Drug-drug interactions involving cytochrome P(450) (CYP) are an important factor in whether a new chemical entity will survive through to the development stage. Therefore, the identification of this potential as early as possible in vitro could save considerable future unnecessary investment. In vitro CYP interaction screening data generated for CYP2C9, CYP2D6, and CYP3A4 were initially analyzed to determine the correlation of IC(50) from 10- and 3-point determinations. A high correlation (r = 0.99) prompted the further assessment of predicting the IC(50) by a single value of percent inhibition at either 10, 3, or 1 microM. Statistical analysis of the initial proprietary compounds showed that there was a strong linear relationship between log IC(50) and percent inhibition at 3 microM, and that it was possible to predict a compound's IC(50) by the percent inhibition value obtained at 3 microM. Additional data for CYP1A2, CYP2C19, and the recombinant CYP2D6 were later obtained and used together with the initial data to demonstrate that a single statistical model could be applicable across different CYPs and different in vitro microsomal systems. Ultimately, the data for all five CYPs and the recombinant CYP2D6 were used to build a statistical model for predicting the IC(50) with a single point. The 95% prediction boundary for the region of interest was about +/- 0.37 on log(10) scale, comparable to the variability of in vitro determinations for positive control IC(50) data. The use of a single inhibitor concentration would enable determination of more IC(50) values on a 96-well plate and result in more economical use of compounds, human liver or expressed enzyme microsomes, substrates, and reagents. This approach would offer the opportunity to increase screening for CYP-mediated drug-drug interactions, which may be important given the challenges provided by the generation of orders of magnitude more new chemical entities in the field of combinatorial chemistry. In addition, the algorithmic approach we propose would obviously be applicable for other in vitro bioactivity and therapeutic target enzyme and receptor screens.