BackgroundA central feature of Alzheimer's disease is the cleavage of the amyloid precursor protein (APP) to form beta-amyloid peptide (Aβ) by the β-secretase and γ-secretase enzymes. Although this has been shown to occur after endocytosis of APP from the cell surface, the exact compartments of APP processing are not well defined. We have previously demonstrated that APP and γ-secretase proteins and activity are highly enriched in purified rat liver lysosomes. In order to examine the lysosomal distribution and trafficking of APP in cultured cells, we generated constructs containing APP fused to a C-terminal fluorescent protein tag and N-terminal HA-epitope tag. These were co-transfected with a panel of fluorescent-protein tagged compartment markers.ResultsHere we demonstrate using laser-scanning confocal microscopy that although APP is present throughout the endosomal/lysosomal system in transfected Cos7 and neuronal SN56 cell lines as well as in immunostained cultured mouse neurons, it is enriched in the lysosome. We also show that the Swedish and London mutations reduce the amount of APP in the lysosome. Surprisingly, in addition to its expected trafficking from the cell surface to the early and then late endosomes, we find that cell-surface labelled APP is transported rapidly and directly from the cell surface to lysosomes in both Cos7 and SN56 cells. This rapid transit to the lysosome is blocked by the presence of either the London or Swedish mutations.ConclusionsThese results demonstrate the presence of a novel, rapid and specific transport pathway from the cell surface to the lysosomes. This suggests that regulation of lysosomal traffic could regulate APP processing and that the lysosome could play a central role in the pathophysiology of Alzheimer's disease.

Non-consensual condom removal (NCCR) is the removal of a condom before or during sexual intercourse without one’s partner's consent. Despite considerable news and media attention devoted to the trend (as stealthing ), little empirical research to date has examined people’s views of the practice. The present study aimed to contribute toward generating empirical evidence to guide the discussion surrounding NCCR. We asked participants about whether or not they felt NCCR is wrong, whether there should be consequences for its perpetration, and contextualized responses within legal context. A total of 592 undergraduate students took part in an online survey inquiring about their experiences with and views of NCCR. We used descriptive statistics to determine sample prevalence and outcomes of NCCR and qualitatively analyzed responses to open-ended questions asking about perceptions of NCCR. Of participants who had engaged in penetrative sexual intercourse with a male partner using an external condom, 18.7%, 95% CI [14.4, 22.7] reported that they had NCCR perpetrated against them. The majority of these participants reported that they experienced NCCR negatively and encountered related consequences; several reported contracting an STI, experiencing an unplanned pregnancy, or both. Nearly all participants expressed that NCCR is wrong, citing reasons that included the lack of consent, possibility of unplanned or unwanted outcomes, and a betrayal of trust. In this study, we found that there was agreement that NCCR is wrong, but variability in responses regarding the circumstances under which there should be consequences for the action. These perceptions reflect the current uncertainty in law. We recommend researchers refer to the phenomenon as NCCR (rather than stealthing ) and discuss related issues to encourage future research to adopt consistent and accurate labels and definitions for NCCR. We hope that our findings will guide future research and spur public and legal discussion on NCCR.

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Inappropriate emergency department (ED) use is costly. A system navigation service was developed to connect individuals with repeated ED presentations due to mental health or substance use to community services. Management, staff, and clients (n = 37) participated in interviews or focus groups to identify implementation challenges and associated solutions. Referrals were improved through ED staff support and automating the process. The outreach process, decreased service duration, and prompt support with connection to services facilitated program delivery. Two newly funded programs addressed the limited capacity of other services, and technology facilitated communication. Attention to partnerships and flexibility in the design were essential.

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