Comparison of Pharmacological Modulation of APP Metabolism in Primary Chicken Telencephalic Neurons and in a Human Neuroglioma Cell Line

Sequential cleavage of amyloid precursor protein (APP) by β- and γ-secretases and the formation of Aβ peptides are pivotal for Alzheimer's disease. Therefore, a large number of drugs has been developed targeting APP metabolism. However, many pharmacological compounds have been identified in vitro in immortalized APP overexpressing cell lines rather than in primary neurons. Here, we compared the effect of already characterized secretase inhibitors and modulators on Aβ formation in primary chicken telencephalic neurons and in a human neuroglioma cell line (H4) ectopically expressing human APP with the Swedish double mutation. Primary chicken neurons replicated the effects of a β-secretase inhibitor (β-secretase inhibitor IV), two γ-secretase inhibitors (DAPM, DAPT), two non-steroidal-anti-inflammatory drugs (sulindac sulfide, CW), and of the calpain inhibitor calpeptin. With the exception of the two γ-secretase inhibitors, all tested compounds were more efficacious in primary chicken telencephalic neurons than in the immortalized H4 cell line. Moreover, H4 cells failed to reproduce the effect of calpeptin. Hence, primary chicken telencephalic neurons represent a suitable cell culture model for testing drugs interfering with APP processing and are overall more sensitive to pharmacological interference than immortalized H4 cells ectopically expressing mutant human APP

An iconic language for the graphical representation of medical concepts

<p>Abstract</p> <p>Background</p> <p>Many medication errors are encountered in drug prescriptions, which would not occur if practitioners could remember the drug properties. They can refer to drug monographs to find these properties, however drug monographs are long and tedious to read during consultation. We propose a two-step approach for facilitating access to drug monographs. The first step, presented here, is the design of a graphical language, called VCM.</p> <p>Methods</p> <p>The VCM graphical language was designed using a small number of graphical primitives and combinatory rules. VCM was evaluated over 11 volunteer general practitioners to assess if the language is easy to learn, to understand and to use. Evaluators were asked to register their VCM training time, to indicate the meaning of VCM icons and sentences, and to answer clinical questions related to randomly generated drug monograph-like documents, supplied in text or VCM format.</p> <p>Results</p> <p>VCM can represent the various signs, diseases, physiological states, life habits, drugs and tests described in drug monographs. Grammatical rules make it possible to generate many icons by combining a small number of primitives and reusing simple icons to build more complex ones. Icons can be organized into simple sentences to express drug recommendations. Evaluation showed that VCM was learnt in 2 to 7 hours, that physicians understood 89% of the tested VCM icons, and that they answered correctly to 94% of questions using VCM (versus 88% using text, <it>p </it>= 0.003) and 1.8 times faster (<it>p </it>< 0.001).</p> <p>Conclusion</p> <p>VCM can be learnt in a few hours and appears to be easy to read. It can now be used in a second step: the design of graphical interfaces facilitating access to drug monographs. It could also be used for broader applications, including the design of interfaces for consulting other types of medical document or medical data, or, very simply, to enrich medical texts.</p

A Genome-wide Haploid Genetic Screen Identifies Regulators of Glutathione Abundance and Ferroptosis Sensitivity

Summary: The tripeptide glutathione suppresses the iron-dependent, non-apoptotic cell death process of ferroptosis. How glutathione abundance is regulated in the cell and how this regulation alters ferroptosis sensitivity is poorly understood. Using genome-wide human haploid genetic screening technology coupled to fluorescence-activated cell sorting (FACS), we directly identify genes that regulate intracellular glutathione abundance and characterize their role in ferroptosis regulation. Disruption of the ATP binding cassette (ABC)-family transporter multidrug resistance protein 1 (MRP1) prevents glutathione efflux from the cell and strongly inhibits ferroptosis. High levels of MRP1 expression decrease sensitivity to certain pro-apoptotic chemotherapeutic drugs, while collaterally sensitizing to all tested pro-ferroptotic agents. By contrast, disruption of KEAP1 and NAA38, leading to the stabilization of the transcription factor NRF2, increases glutathione levels but only weakly protects from ferroptosis. This is due in part to concomitant NRF2-mediated upregulation of MRP1. These results pinpoint glutathione efflux as an unanticipated regulator of ferroptosis sensitivity. : Glutathione suppresses the non-apoptotic cell death process of ferroptosis. Using genome-wide human haploid cell mutagenesis and FACS-based detection, Cao et al. identify negative regulators of intracellular glutathione abundance that affect glutathione efflux and NRF2 protein levels, altering ferroptosis sensitivity. Keywords: ROS, metabolite efflux, multidrug resistance, ferroptosis, necrosis, cancer, glutathione, iron, collateral sensitivit

Avatar Obama in the age of liquid celebrity

Barak Obama, orator extraordinaire, the embodiment of the American success myth, \u27global\u27 prophet of the adoring masses and multi-media auratic figure, is the leading illustration of what is the expanded nexus of celebrity, spectacle and politics in the age of what Zygmund Bauman refers to as liquid modernity or \u27the era of disembedding without re-embedding\u27 (2001, p. 89). This is the era in which a traumatic sense of fear, uncertainty and transience defines one\u27s relationship to the nation state, and social (media) centre, as they lose their economic singularity and cultural coherency and cohesiveness in a world system ever inter-connected and driven increasingly, incessantly by supra-corporate concerns and spectacular celebrity-based presentations. In this world of \u27togetherness dismantled\u27 (Bauman 2003, p. 119), the disenfranchised individual feels they cannot meet the trans-capital intensive, show reel-like, boundaryless world on solid ground. That adoration, or a liquefied definition of it, is key to this imagined and affective communion between Obama and those who adore him, suggests that there is a terrible wanting and simultaneous waning to those who look for such rootedness and the promise of deliverance in the celebrity political figure. This is a charismatic authority figure who promises this solidity yet streams in and out of material view, unable to fix or properly propagate their communion beyond triumphant spectacularism. Their \u27lightness of being\u27 (ibid, p. 123-9) is powerfully seductive and decidedly empty because it echoes the instantaneous (instant) way in which all lives are increasingly led. I will suggest that liquid celebrity is one of the cornerstones of liquid modernity, and Barack Obama is the epitome of this \u27runniness\u27

Honey bee Royalactin unlocks conserved pluripotency pathway in mammals

Royal jelly is the queen-maker for the honey bee that also has effects on longevity, fertility, and regeneration in mammals. Here the authors provide evidence that its major protein component Royalactin, and the mammalian structural analog Regina, maintain pluripotency in mouse ESCs by activating a ground-state pluripotency-like gene network

Alterations in taste perception due to recreational drug use are due to smoking a substance rather than ingesting it

Two studies explored the differences in tastant (salt, sour, bitter, sweet and spicy) concentration preference between recreational drug users and abstainers. In study 1, 250 opportunistically recruited abstainers, cannabis only users and multiple-drug users completed psychometric questionnaires and a concentration preference tastant test. In study 2, 76 participants purposefully recruited abstainers, daily tobacco users, recreational cannabis users and daily cannabis users completed the same protocol as study 1. Study 1 demonstrated that both multiple drug users and cannabis users had a higher preference for salt and sour tastants than abstainers. Study 2 showed that daily cannabis and tobacco users had a higher preference for sweet and spicy tastants than recreational cannabis users and abstainers. As predicted, recreational drug users scored higher on both sensation-seeking and impulsivity compared to abstainers. Participants who habitually smoke tobacco or cannabis daily have different concentration preference for specific tastants. The aim of the current study was to provide an explanation for the inconsistency in published results on taste preferences in recreational drug users. The data offered in this paper indicate that variation in recruitment strategy, definition of ‘drug users’, and mode of drug delivery, as well as multiple drug use, may explain the preference for stronger tastants in habitual drug users. Future research exploring the psychobiological underpinnings of the impact of drug use on food preferences should carefully define recreational drug user groups