Integration of GPCR Signaling and Sorting from Very Early Endosomes via Opposing APPL1 Mechanisms.

Endocytic trafficking is a critical mechanism for cells to decode complex signaling pathways, including those activated by G-protein-coupled receptors (GPCRs). Heterogeneity in the endosomal network enables GPCR activity to be spatially restricted between early endosomes (EEs) and the recently discovered endosomal compartment, the very early endosome (VEE). However, the molecular machinery driving GPCR activity from the VEE is unknown. Using luteinizing hormone receptor (LHR) as a prototype GPCR for this compartment, along with additional VEE-localized GPCRs, we identify a role for the adaptor protein APPL1 in rapid recycling and endosomal cAMP signaling without impacting the EE-localized ß2-adrenergic receptor. LHR recycling is driven by receptor-mediated Gαs/cAMP signaling from the VEE and PKA-dependent phosphorylation of APPL1 at serine 410. Receptor/Gαs endosomal signaling is localized to microdomains of heterogeneous VEE populations and regulated by APPL1 phosphorylation. Our study uncovers a highly integrated inter-endosomal communication system enabling cells to tightly regulate spatially encoded signaling.

Effects of microRNA-146a on the proliferation and apoptosis of human osteochondrocytes by targeting TRAF6 through the NF- κB signalling pathway.

MicroRNAs are important cellular mediators of mRNA degradation and translation repression, which in turn can have an impact on various processes and, if their function is perturbed, can cause disease. Here, we summarize the recent manuscript by Zhong et al. [(2017) Biosci. Rep. 37, BSR20160578], which explores microRNA-146a and how it may play an indirect yet vital role in the proliferation of osteoarthritis (OA) chondrocytes. The data presented by the authors could have important implications for future OA therapies.

Expert opinion on risks to the long-term viability of residential recycled water schemes: An Australian study.

The water sector needs to make efficient and prudent investment decisions by carefully considering the long-term viability of water infrastructure projects. To support the assessment and planning of residential recycled water schemes in Australia, we have sought to clarify scheme objectives and to further define the array of critical risks that can impact the long-term viability of schemes. Building on historical information, we conducted a national survey which elicited responses from 88 Australian expert practitioners, of which 64% have over 10 years of industry experience and 42% have experience with more than five residential recycled water schemes. On the basis of expert opinion, residential recycled water schemes are considered to be highly relevant for diversifying and improving water supply security, reducing wastewater effluent discharge and pollutant load to waterways and contributing to sustainable urban development. At present however, the inability to demonstrate an incontestable business case is posing a significant risk to the long-term viability of residential recycled water schemes. Political, regulatory, organisational and financial factors were also rated as critical risks, in addition to community risk perception and fall in demand. The survey results shed further light on the regulatory environment of residential recycled water schemes, with regulatory participants rating the level and impact of risk factors higher than other survey participants in most cases. The research outcomes provide a comprehensive understanding of the critical risks to the long-term viability of residential recycled water schemes, thereby enabling the specification of targeted risk management measures at the assessment and planning stage of a scheme.

Why do residential recycled water schemes fail? A comprehensive review of risk factors and impact on objectives.

In Australia, recycled water schemes have been implemented in residential developments to contribute to sustainable urban development, improve water supply security and reduce pollutant discharges to the environment. A proportion of these schemes, however, have been decommissioned well before the end of their design life which raises questions about the adequacy of the risk assessment and management practices adopted for recycled water schemes. Through a detailed literature review, an investigation of 21 residential recycled water schemes and in-depth interviews with nine scheme stakeholders, we identified 34 risk factors arising from six sources which have the potential to impact the long-term viability of residential recycled water schemes. Of the 34 risk factors identified, 17 were reported to have occurred during the development and implementation of the 21 schemes investigated. The overall risk rating of the 17 factors was qualitatively defined on the basis of the likelihood of occurrence and the impact of the risk factors on the scheme objectives. The outcomes of the assessment indicate that the critical risks to the long-term viability of residential recycled water schemes are 1. unanticipated operational costs, 2. legal and contractual arrangements, 3. regulatory requirements and approval process and 4. customer complaints and expectations not met. To date, public health risks associated with the provision of recycled water have been of primary concern, though the outcomes of this study indicate that the impact to public health has been low. Evidently there is a need for improved assessment and management practices which address the range of critical risk factors, in addition to the routine consideration of public health risks.

Minireview: Spatial Programming of G Protein-Coupled Receptor Activity: Decoding Signaling in Health and Disease.

Probing the multiplicity of hormone signaling via G protein-coupled receptors (GPCRs) has demonstrated the complex signal pathways that underlie the multiple functions these receptors play in vivo. This is highly pertinent for the GPCRs key in reproduction and pregnancy that are exposed to cyclical and dynamic changes in their extracellular milieu. How such functional pleiotropy in GPCR signaling is translated to specific downstream cellular responses, however, is largely unknown. Emerging data strongly support mechanisms for a central role of receptor location in signal regulation via membrane trafficking. In this review, we discuss current progress in our understanding of the role membrane trafficking plays in location control of GPCR signaling, from organized plasma membrane signaling microdomains, potentially provided by both distinct endocytic and exocytic pathways, to more recent evidence for spatial control within the endomembrane system. Application of these emerging mechanisms in their relevance to GPCR activity in physiological and pathophysiological conditions will also be discussed, and in improving therapeutic strategies that exploits these mechanisms in order to program highly regulated and distinct signaling profiles.

The membrane free sonoelectroanalytical determination of trace levels of lead and cadmium in human saliva.

In this paper, square wave anodic stripping voltammetry (SWASV), synergistically coupled with an ultrasonically enhanced preconcentration step has been shown to yield a quantitative determination of lead and cadmium in human saliva at a membrane free in situ plated mercury thin film glassy carbon electrode. The sensitivity was facilitated by acoustic streaming which promoted efficient mass transport to the electrode thus reducing sampling times. Cavitation was responsible for cleaning and activating the electrode surface, this was essential in order to obtain a reproducible and representative signal. In silent conditions electrode fouling leading to fluctuations in the baseline current and signal depression, precluded accurate quantitative analyses. The results presented herein provide an extension to the proof of concept given in the authors' earlier work, with the analysis of lead in human saliva as opposed to artificial saliva reported. We also address the hitherto unreported detection and determination of cadmium in this medium. Results for both were independently verified by inductively coupled plasma-mass spectroscopy (ICP-MS). Close agreement between lead concentration determined by sono-SWASV and independent and blind ICP-MS is reported for human saliva samples having a total lead content of 0.92 microg L(-1) and 5 microg L(-1) with a detection limit of 0.5 microg L(-1). Microaddition calibration data for cadmium additions of 0.0125 microg L(-1) to samples spiked with 2.5 microg L(-1) and 5.0 microg L(-1) (reflecting levels in workers occupationally exposed) exhibited close agreement with the known total cadmium in the samples. A detection limit of 1 microg L(-1) cadmium in saliva has been established.