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In the midst of an escalating U.S. opioid crisis, the immediate focus of public health interventions is on fatal overdose prevention. Few studies, however, have sought to examine the long-term health consequences of exposure to repeated nonfatal opioid overdose. We reviewed recent literature to examine three corresponding downstream health outcomes of repeated overdose: a) neurodegenerative processes; b) cognition and memory; and c) overdose risk behaviours. We found a remarkable congruency among available biochemical and cognitive data on how nonfatal overdose precipitates various pathological feedforward and feedback loops that affect people who use opioids for years to come. We found however that downstream behavioural implications of neurodegenerative and cognitive sequelae are less studied despite being most proximal to an overdose. Findings point to a vicious cycle of nonfatal overdose leading to neurodegeneration - closely resembling Alzheimer Disease - that results in cognitive decline that in turn leads to potentially reduced adherence to safe drug use behaviours. The collected evidence not only brings into the focus the long-term health consequences of nonfatal overdose from the perspectives of biology, neuroscience, and public health, but also creates new cross-disciplinary context and awareness in the research and public health community that should benefit people at risk., Competing Interests: Declarations of Interest All authors [Voronkov, Ataiants, Cocchiaro, Stock, Lankenau] declare no conflicts of interest., (Copyright © 2021. Published by Elsevier B.V.)

A minor component of coffee unrelated to caffeine, eicosanoyl-5-hydroxytryptamide (EHT), provides protection in a rat model for Alzheimer's disease (AD). In this model, viral expression of the phosphoprotein phosphatase 2A (PP2A) endogenous inhibitor, the I2(PP2A), or SET protein in the brains of rats leads to several characteristic features of AD including cognitive impairment, tau hyperphosphorylation, and elevated levels of cytoplasmic amyloid-β protein. Dietary supplementation with EHT for 6-12 months resulted in substantial amelioration of all these defects. The beneficial effects of EHT could be associated with its ability to increase PP2A activity by inhibiting the demethylation of its catalytic subunit PP2Ac. These findings raise the possibility that EHT may make a substantial contribution to the apparent neuroprotective benefits associated with coffee consumption as evidenced by numerous epidemiologic studies indicating that coffee drinkers have substantially lowered risk of developing AD., (Copyright © 2014 Elsevier Inc. All rights reserved.)

N-acetyl-S-farnesyl-L-cysteine (AFC), a modulator of G protein and G-protein coupled receptor signaling, inhibits neutrophil chemotaxis and other inflammatory responses in cell-based assays. Here, we show topical AFC inhibits in vivo acute inflammation induced by 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and arachidonic acid using the mouse ear model of inflammation. AFC inhibits edema, as measured by ear weight, and also inhibits neutrophil infiltration as assayed by direct counting in histological sections and by measuring myeloperoxidase (MPO) activity as a neutrophil marker. In addition, AFC inhibits in vivo allergic contact dermatitis in a mouse model utilizing sensitization followed by a subsequent challenge with 2,4-dinitrofluorobenzene. Unlike the established anti-inflammatories dexamethasone and indomethacin, AFC's action was restricted to the site of application. In this mouse model, both dexamethasone and indomethacin inhibited TPA-induced edema and MPO activity in the vehicle-treated, contralateral ear. AFC showed no contralateral ear inhibition for either of these end points. A marginally significant decrease due to AFC treatment was seen in TPA-induced epidermal hyperplasia at 24 hours. This was much less than the 90% inhibition of neutrophil infiltration, suggesting that AFC does not act by directly inhibiting protein kinase C.

A key event in Dictyostelium development is the formation of the Mexican hat. This corresponds to a commitment step in morphogenesis that irreversibly signals progression from the slug stage to the fruiting body. We describe the characterization of the dhkK gene that controls this morphogenetic step. Null mutants of dhkK repeatedly attempt, and fail, to undergo morphogenesis from the slug to the Mexican hat, causing them to exhibit a "slugger" phenotype, which cannot be corrected by co-development with wild-type cells. The dhkK gene encodes a putative receptor histidine kinase whose expression is enriched in prestalk cells in the slug. Uniquely for a histidine kinase, DhkK is located in the nuclear envelope. Entry into culmination requires the DhkK response regulator domain, which appears to directly regulate cyclic AMP signaling.